3-alkoxy, thioalkyl and amino-4-amino-6-(substituted)picolinates and their use as herbicides

ABSTRACT

3-alkoxy, thioalkyl and amino-4-amino-6-(substituted)picolinic acids having a halogen, alkyl or mono-, di-tri- and tetra-substituted aryl substituents in the 6-position, and their acid derivatives, are herbicides demonstrating a broad spectrum of weed control.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 13/538,399filed Jun. 29, 2012, which claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/502,888, filed Jun. 30, 2011.

FIELD OF THE INVENTION

This invention relates to certain 3-alkoxy, thioalkyl andamino-4-amino-6-(substituted)picolinates and their derivatives and tothe use of these compounds as herbicides.

BACKGROUND OF THE INVENTION

A number of picolinic acids and their pesticidal properties have beendescribed in the art. U.S. Patent Application Publication 2005/0176767discloses 3-substituted-4-amino-6-substituted picolinamides as humanimmunodeficiency virus (HIV) integrase inhibitors. U.S. Pat. No.6,297,197 B2 discloses 3-substituted-4-amino-6-(substituted)picolinicacids and their derivatives and their use as herbicides. JP 2007204458 Aand WO 2007020936 A1 disclose compounds that have uses as antimycotic orantifungal agents. U.S. Pat. Nos. 6,784,137 B2 and 7,314,849 B2 disclosea genus of 6-aryl-4-aminopicolinic acids and their derivatives and theiruse as herbicides. U.S. Pat. Nos. 7,300,907 B2 and 7,642,220 B2 disclosea genus of 2-aryl-6-amino-5-alkoxy-4-pyrimidinecarboxylic acids andtheir derivatives and their use as herbicides. It has now beendiscovered that 3-alkoxy, thioalkyl andamino-4-amino-6-(substituted)picolinates exhibit similar herbicidalactivity and selectivity.

SUMMARY OF THE INVENTION

Certain 3-alkoxy, thioalkyl and amino-4-amino-6-(substituted)picolinicacids and their derivatives are herbicides with a broad spectrum of weedcontrol against a variety of weeds, including grasses, broadleaves andsedges.

Provided herein are compound of Formula A:

wherein

Q represents C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, SR³, or NR¹R²;

X represents H or halogen;

Y represents F, Cl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₃-C₇ cycloalkyl, C₃-C₇ halocycloalkyl or Ar;

Ar represents a phenyl group or a pyridine substituted with one to foursubstituents independently selected from halogen, nitro, cyano, formyl,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₂-C₄ alkoxyalkyl, C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₄ alkenyloxy, C₂-C₄ alkynloxy,C₂-C₄ alkenylthio, C₂-C₄ alkynylthio, C₁-C₆ haloalkyl, C₃-C₇halocycloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl, C₁-C₆ haloalkoxy,C₂-C₄ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl,C₂-C₄ haloalkenyloxy, C₂-C₄ haloalkynyloxy, C₂-C₄ haloalkenylthio, C₂-C₄haloalkynylthio, —OCH₂CH₂—, —OCH₂CH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —C(O)OR³,—C(O)NR³R⁴, —CR⁴NOR³, —NH₂, —NR³R⁴, —NR⁴OR³, —NR⁴SO₂R³, —NR⁴C(O)R³,—NR⁴C(O)OR³, —NR⁴C(O)NR³R⁴ or —NCR⁴NR³R⁴;

R¹ and R² independently represent H, C₁-C₆ alkyl, or C₁-C₆ acyl;

R³ represents C₁-C₄ alkyl or C₁-C₄ haloalkyl; and

R⁴ represents H, C₁-C₄ alkyl or C₁-C₄ haloalkyl;

and agriculturally acceptable derivatives of the carboxylic acid groupof the picolinic acid.

In some embodiments, the compound of Formula A is a compound of FormulaI:

wherein

Q represents C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;

X represents H or halogen;

Y represents F, Cl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₃-C₇ cycloalkyl, C₃-C₇ halocycloalkyl or Ar;

Ar represents a phenyl group or a pyridine substituted with one to foursubstituents independently selected from halogen, nitro, cyano, formyl,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₂-C₄ alkoxyalkyl, C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₄ alkenyloxy, C₂-C₄ alkynloxy,C₂-C₄ alkenylthio, C₂-C₄ alkynylthio, C₁-C₆ haloalkyl, C₃-C₇halocycloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl, C₁-C₆ haloalkoxy,C₂-C₄ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl,C₂-C₄ haloalkenyloxy, C₂-C₄ haloalkynyloxy, C₂-C₄ haloalkenylthio, C₂-C₄haloalkynylthio, —OCH₂CH₂—, —OCH₂CH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —C(O)OR³,—C(O)NR³R⁴, —CR⁴NOR³, —NH₂, —NR³R⁴, —NR⁴OR³, —NR⁴SO₂R³, —NR⁴C(O)R³,—NR⁴C(O)OR³, —NR⁴C(O)NR³R⁴ or —NCR⁴NR³R⁴;

R¹ and R² independently represent H, C₁-C₆ alkyl, or C₁-C₆ acyl;

R³ represents C₁-C₄ alkyl or C₁-C₄ haloalkyl; and

R⁴ represents H, C₁-C₄ alkyl or C₁-C₄ haloalkyl;

and agriculturally acceptable derivatives of the carboxylic acid groupof the picolinic acid.

Preferred compounds of Formula A and Formula I independently includethose in which Q represents methoxy, X represents H or F, Y representsAr, Ar represents para-substituted phenyl with or without othersubstituents, and R¹ and R² represent H.

The invention includes herbicidal compositions comprising anherbicidally effective amount of a compound of Formula A andagriculturally acceptable derivatives of the carboxylic acid group inadmixture with an agriculturally acceptable adjuvant or carrier. Theinvention also includes a method of use of the compounds andcompositions of the present invention to kill or control undesirablevegetation by application of an herbicidal amount of the compound to thevegetation or to the locus of the vegetation as well as to the soil orwater prior to emergence of the vegetation.

In some embodiments, the compound of Formula A is a compound of FormulaI*:

wherein

Q represents SR³ or NR₁R₂;

X represents H or halogen;

Y represents F, Cl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₃-C₇ cycloalkyl, C₃-C₇ halocycloalkyl or Ar;

Ar represents a phenyl group or a pyridine substituted with one to foursubstituents independently selected from halogen, nitro, cyano, formyl,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₂-C₄ alkoxyalkyl, C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₄ alkenyloxy, C₂-C₄ alkynloxy,C₂-C₄ alkenylthio, C₂-C₄ alkynylthio, C₁-C₆ haloalkyl, C₃-C₇halocycloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl, C₁-C₆ haloalkoxy,C₂-C₄ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl,C₂-C₄ haloalkenyloxy, C₂-C₄ haloalkynyloxy, C₂-C₄ haloalkenylthio, C₂-C₄haloalkynylthio, —OCH₂CH₂—, —OCH₂CH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —C(O)OR³,—C(O)NR³R⁴, —CR⁴NOR³, —NH₂, —NR³R⁴, —NR⁴OR³, —NR⁴SO₂R³, —NR⁴C(O)R³,—NR⁴C(O)OR³, —NR⁴C(O)NR³R⁴ or —NCR⁴NR³R⁴;

R¹ and R² independently represent H, C₁-C₆ alkyl, or C₁-C₆ acyl;

R³ represents C₁-C₄ alkyl or C₁-C₄ haloalkyl;

R⁴ represents H, C₁-C₄ alkyl or C₁-C₄ haloalkyl; and

and agriculturally acceptable derivatives of the carboxylic acid groupof the picolinic acid.

The invention also includes compounds of the Formula II

wherein

Q represents H or I; and

Y represents a phenyl group substituted with one to four substitutentsindependently selected from halogen, C₁-C₆ alkoxy or C₁-C₆ haloalkyl;

and C₁-C₁₂ esters of the carboxylic acid group of the picolinic acid.

The invention also includes compounds of the Formula III

wherein

n is 1 or 2; and

R⁹ and R¹⁰ independendently represent C₁-C₄ alkyl or R⁹ and R¹⁰ takentogether represent an ethylene (—CH₂CH₂—) or propylene (—CH₂CH₂CH₂—)bridge optionally substituted with from 1 to 4 methyl groups.

The invention also includes compounds of the Formula IV

wherein

W represents Br or NH₂;

Z represents Br or a phenyl group substituted with one to foursubstitutents independently selected from halogen, C₁-C₆ alkoxy or C₁-C₆haloalkyl; and R¹¹ represents H or —CHF₂.

The invention also includes compounds of the Formula V

wherein

Ar represents a phenyl group substituted with one to four substitutentsindependently selected from halogen, C₁-C₆ alkoxy or C₁-C₆ haloalkyl;

and C₁-C₁₂ esters of the carboxylic acid group of the picolinic acid.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compounds of Formula A:

wherein

Q represents C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, SR³, or NR¹R²;

X represents H or halogen;

Y represents F, Cl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₃-C₇ cycloalkyl, C₃-C₇ halocycloalkyl or Ar;

Ar represents a phenyl group or a pyridine substituted with one to foursubstituents independently selected from halogen, nitro, cyano, formyl,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₂-C₄ alkoxyalkyl, C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₄ alkenyloxy, C₂-C₄ alkynloxy,C₂-C₄ alkenylthio, C₂-C₄ alkynylthio, C₁-C₆ haloalkyl, C₃-C₇halocycloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl, C₁-C₆ haloalkoxy,C₂-C₄ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl,C₂-C₄ haloalkenyloxy, C₂-C₄ haloalkynyloxy, C₂-C₄ haloalkenylthio, C₂-C₄haloalkynylthio, —OCH₂CH₂—, —OCH₂CH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —C(O)OR³,—C(O)NR³R⁴, —CR⁴NOR³, —NH₂, —NR³R⁴, —NR⁴OR³, —NR⁴SO₂R³, —NR⁴C(O)R³,—NR⁴C(O)OR³, —NR⁴C(O)NR³R⁴ or —NCR⁴NR³R⁴;

R¹ and R² independently represent H, C₁-C₆ alkyl, or C₁-C₆ acyl;

R³ represents C₁-C₄ alkyl or C₁-C₄ haloalkyl; and

R⁴ represents H, C₁-C₄ alkyl or C₁-C₄ haloalkyl;

and agriculturally acceptable derivatives of the carboxylic acid groupof the picolinic acid.

In some embodiments, Q is C₁-C₄ alkoxy.

In some embodiments, Q is methoxy.

In some embodiments, Q is NH₂.

In some embodiments, X is H or F.

In some embodiments, Y is Ar. In certain embodiments, Ar representspara-substituted phenyl with or without other substituents. Inparticular embodiments, the para-substituted phenyl has no othersubstitutents. In particular embodiments, the para-substituted phenylhas one other substitutent. In particular embodiments, thepara-substituted phenyl has two other substitutents. In particularembodiments, the para-substituted phenyl has three other substitutents.In particular embodiments, the para-substituted phenyl has four othersubstitutents. In certain embodiments, the other substituent(s) ishalogen or C₁₋₆ alkoxy.

In some embodiments, Q represents methoxy, X represents H or F, Yrepresents Ar, Ar represents para-substituted phenyl with or withoutother substituents, and R¹ and R² represent H.

In some embodiments, the compound of Formula A is a compound of FormulaI:

wherein

Q represents C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;

X represents H or halogen;

Y represents F, Cl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₃-C₇ cycloalkyl, C₃-C₇ halocycloalkyl or Ar;

Ar represents a phenyl group or a pyridine substituted with one to foursubstituents independently selected from halogen, nitro, cyano, formyl,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₂-C₄ alkoxyalkyl, C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₄ alkenyloxy, C₂-C₄ alkynloxy,C₂-C₄ alkenylthio, C₂-C₄ alkynylthio, C₁-C₆ haloalkyl, C₃-C₇halocycloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl, C₁-C₆ haloalkoxy,C₂-C₄ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl,C₂-C₄ haloalkenyloxy, C₂-C₄ haloalkynyloxy, C₂-C₄ haloalkenylthio, C₂-C₄haloalkynylthio, —OCH₂CH₂—, —OCH₂CH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —C(O)OR³,—C(O)NR³R⁴, —CR⁴NOR³, —NH₂, —NR³R⁴, —NR⁴OR³, —NR⁴SO₂R³, —NR⁴C(O)R³,—NR⁴C(O)OR³, —NR⁴C(O)NR³R⁴ or —NCR⁴NR³R⁴;

R¹ and R² independently represent H, C₁-C₆ alkyl, or C₁-C₆ acyl;

R³ represents C₁-C₄ alkyl or C₁-C₄ haloalkyl; and

R⁴ represents H, C₁-C₄ alkyl or C₁-C₄ haloalkyl;

and agriculturally acceptable derivatives of the carboxylic acid groupof the picolinic acid.

In some embodiments, the compound of Formula A is a compound of FormulaI*:

wherein

Q represents SR³ or NR₁R₂;

X represents H or halogen;

Y represents F, Cl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₃-C₇ cycloalkyl, C₃-C₇ halocycloalkyl or Ar;

Ar represents a phenyl group or a pyridine substituted with one to foursubstituents independently selected from halogen, nitro, cyano, formyl,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₂-C₄ alkoxyalkyl, C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₄ alkenyloxy, C₂-C₄ alkynloxy,C₂-C₄ alkenylthio, C₂-C₄ alkynylthio, C₁-C₆ haloalkyl, C₃-C₇halocycloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl, C₁-C₆ haloalkoxy,C₂-C₄ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl,C₂-C₄ haloalkenyloxy, C₂-C₄ haloalkynyloxy, C₂-C₄ haloalkenylthio, C₂-C₄haloalkynylthio, —OCH₂CH₂—, —OCH₂CH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —C(O)OR³,—C(O)NR³R⁴, —CR⁴NOR³, —NH₂, —NR³R⁴, —NR⁴OR³, —NR⁴SO₂R³, —NR⁴C(O)R³,—NR⁴C(O)OR³, —NR⁴C(O)NR³R⁴ or —NCR⁴NR³R⁴;

R¹ and R² independently represent H, C₁-C₆ alkyl, or C₁-C₆ acyl;

R³ represents C₁-C₄ alkyl or C₁-C₄ haloalkyl;

R⁴ represents H, C₁-C₄ alkyl or C₁-C₄ haloalkyl; and

and agriculturally acceptable derivatives of the carboxylic acid groupof the picolinic acid.

In certain embodiments, these compounds are characterized by possessinga carboxylic acid group or a derivative thereof in the 2-position; analkoxy, haloalkoxy, thioalkyl, amino, or aminoalkyl group in the3-position; an amino or substituted amino group in the 4-position; and asubstituent, preferably a mono-, di-, tri- or tetra-substituted phenylor pyridyl group, in the 6-position of the pyridine ring. Compounds inwhich methoxy is in the 3-position of the pyridine ring are generallypreferred. Preferred substituted aryl groups include para-substitutedphenyl with or without other substituents.

Without being limited to any theory, the carboxylic acids of Formula Aare believed to be the compounds that actually kill or controlundesirable vegetation and are typically preferred. Analogs of thesecompounds in which the acid group of the picolinic acid is derivatizedto form a related substituent that can be transformed within plants orthe environment to an acid group possess essentially the same herbicidaleffect and are within the scope of the invention. Therefore, an“agriculturally acceptable derivative,” when used to describe thecarboxylic acid functionality at the 2-position, is defined as any salt,ester, acylhydrazide, imidate, thioimidate, amidine, amide, orthoester,acylcyanide, acyl halide, thioester, thionoester, dithiolester, nitrileor any other acid derivative well known in the art which (a) does notsubstantially affect the herbicidal activity of the active ingredient,e.g., a 3-alkoxy, thioalkyl and amino-4-amino-6-(substituted)picolinicacid described herein, and (b) is or can be hydrolyzed, oxidized ormetabolized in plants or soil to the picolinic acid of Formula A that,depending upon the pH, is in the dissociated or the undissociated form.The preferred agriculturally acceptable derivatives of the carboxylicacid are agriculturally acceptable salts, esters and amides. In someembodiments, the agriculturally acceptable deriviative is an C₁₋₈ alkylester or C₆₋₁₂ arylalkyl ester, e.g, benzyl ester.

Suitable salts include those derived from alkali or alkaline earthmetals and those derived from ammonia and amines. Preferred cationsinclude sodium, potassium, magnesium, and aminium cations of theformula:R⁵R⁶R⁷R⁸N⁺wherein R⁵, R⁶, R⁷ and R⁸ each, independently represents hydrogen orC₁-C₁₂ alkyl, C₃-C₁₂ alkenyl or C₃-C₁₂ alkynyl, each of which isoptionally substituted by one or more hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio or phenyl groups, provided that R⁵, R⁶, R⁷ and R⁸ aresterically compatible. Additionally, any two of R⁵, R⁶, R⁷ and R⁸together may represent an aliphatic difunctional moiety containing oneto twelve carbon atoms and up to two oxygen or sulfur atoms. Salts ofthe compounds described herein can be prepared by treatment of thecompound with a metal hydroxide, such as sodium hydroxide, with anamine, such as ammonia, trimethylamine, diethanolamine,2-methylthiopropylamine, bisallylamine, 2-butoxyethylamine, morpholine,cyclododecylamine, or benzylamine or with a tetraalkylammoniumhydroxide, such as tetramethylammonium hydroxide or choline hydroxide.Amine salts are often preferred forms of the compounds of describedherein because they are water-soluble and lend themselves to thepreparation of desirable aqueous based herbicidal compositions.

Suitable esters include those derived from C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl,C₃-C₁₂ alkynyl or C₇-C₁₀ aryl-substituted alkyl alcohols, such as methylalcohol, isopropyl alcohol, 1-butanol, 2-ethylhexanol, butoxyethanol,methoxypropanol, allyl alcohol, propargyl alcohol, cyclohexanol orunsubstituted or substituted benzyl alcohols. Benzyl alcohols may besubstituted with from 1-3 substituents independently selected fromhalogen, C₁-C₄ alkyl or C₁-C₄ alkoxy. Esters can be prepared by couplingof the picolinic acids with the alcohol using any number of suitableactivating agents such as those used for peptide couplings such asdicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI); byreacting the picolinic acids with alkylating agents such as alkylhalidesor alkylsulfonates in the presence of a base such as triethylamine orlithium carbonate; by reacting the corresponding acid chloride of apicolinic acid of Formula A with an appropriate alcohol; by reacting thecorresponding picolinic acid of Formula A with an appropriate alcohol inthe presence of an acid catalyst or by transesterification.

Suitable amides include those derived from ammonia or from C₁-C₁₂ alkyl,C₃-C₁₂ alkenyl or C₃-C₁₂ alkynyl mono- or di-substituted amines, such asbut not limited to dimethylamine, diethanolamine,2-methylthiopropylamine, bisallylamine, 2-butoxyethylamine,cyclododecylamine, benzylamine or cyclic or aromatic amines with orwithout additional heteroatoms such as but not limited to aziridine,azetidine, pyrrolidine, pyrrole, imidazole, tetrazole or morpholine,unsubstituted or substituted. Amides can be prepared by reacting thecorresponding picolinic acid chloride, mixed anhydride, or carboxylicester of Formula A with ammonia or an appropriate amine.

The term “alkyl,” “aryl-substituted alkyl,” “alkenyl” and “alkynyl,” aswell as derivative terms such as “alkoxy,” “acyl,” “alkylthio” and“alkylsulfonyl,” as used herein, include within their scope straightchain, branched chain and cyclic moieties, unsubstituted or substituted.The terms “alkenyl” and “alkynyl” are intended to include one or moreunsaturated bonds.

The term “aryl,” as well as derivative terms such as “aryloxy,” refersto a phenyl group or a pyridine group substituted with one to foursubstitutents selected from halogen, nitro, cyano, formyl, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₂-C₄alkoxyalkyl, C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl,C₁-C₆ alkylsulfonyl, C₂-C₄ alkenyloxy, C₂-C₄ alkynloxy, C₂-C₄alkenylthio, C₂-C₄ alkynylthio, C₁-C₆ haloalkyl, C₃-C₇ halocycloalkyl,C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl, C₁-C₆ haloalkoxy, C₂-C₄haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio, C₁-C₆haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₂-C₄haloalkenyloxy, C₂-C₄ haloalkynyloxy, C₂-C₄ haloalkenylthio, C₂-C₄haloalkynylthio, —OCH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —C(O)OR³,—C(O)NR³R⁴, —CR⁴NOR³, —NH₂, —NR³R⁴, —NR⁴OR³, —NR⁴SO₂R³, —NR⁴C(O)R³,—NR⁴C(O)OR³, —NR⁴C(O)NR³R⁴ or —NCR⁴NR³R⁴.

Unless specifically limited otherwise, the term “halogen” includingderivative terms such as “halo” refers to fluorine, chlorine, bromineand iodine. The terms “haloalkyl” and “haloalkoxy” refer to alkyl andalkoxy groups substituted with from 1 to the maximum possible number ofhalogen atoms.

The compounds of Formula A, e.g., I and I*, can be made using well-knownchemical procedures. The required starting materials are commerciallyavailable or readily synthesized utilizing standard procedures.

The 3-alkoxy-4-amino-6-(substituted)picolinates of Formula A, e.g., Iand I*, can be prepared in a number of ways. The3-methoxy-6-chloropicolinate of Formula II can be oxidized to thecorresponding pyridine N-oxide of Formula III, as in step a of Scheme I,using urea hydrogen peroxide complex and trifluoroacetic anhydride in anon-reactive solvent such as dichloromethane at a temperature from 0 to20° C. Chlorination of the pyridine N-oxide of Formula III can beachieved using phosphorus oxychloride at 70 to 100° C., as in step b ofScheme I, to provide a 1:1 mixture of the 5,6- and4,6-dichloro-3-methoxypicolinates, which after chromatography yields the4,6-dichloropicolinate of Formula IV. In step c₁, the 4-chloro group canbe displaced with sodium azide in a polar, aprotic solvent such asN,N-dimethylformamide (DMF) at 50° C. The resulting 4-azido compound canbe reduced with sodium borohydride in a polar, protic solvent such asmethyl alcohol to give the 4-aminopicolinate of Formula I-A, as in stepd₁ of Scheme I. Further chlorination of the 4-aminopicolinate of FormulaI-A can be accomplished with sulfuryl chloride in a polar, aproticsolvent such as acetonitrile, as in step e of Scheme I, to afford the5,6-dichloropicolinate of Formula I-B.

In step f₁ of Scheme II, the 6-bromopicolinate of Formula V (synthesizedby the procedures found in Kong, L. C. C. et al. WO 2005042524 (2005))can be converted to the 6-arylpicolinate of Formula VI, wherein Ar is aspreviously defined, via Suzuki coupling with a boronic acid or ester, inthe presence of a catalyst such as bis(triphenylphosphine)-palladium(II)dichloride, cesium fluoride and a polar protic solvent mixture such as1,2-dimethoxyethane-water at 100° C. in a microwave reactor. The benzylgroup can be removed from the compound of Formula VI via hydrogenolysiswith hydrogen gas, in the presence of a catalyst such as palladiumhydroxide on carbon in a polar, protic solvent such as ethyl alcohol toprovide the 3-hydroxypicolinate of Formula VII, wherein Ar is aspreviously defined, as in step g of Scheme II. In step h, the 3-hydroxygroup can be transformed via reaction with triphenylphosphine anddiethyl azodicarboxylate in a polar, protic solvent such as methylalcohol to afford the 3-methoxypicolinate of Formula I-C, wherein Ar isas previously defined. Removal of the 4-acetyl protecting group from thecompound of Formula I-C can be accomplished by reaction with acetylchloride in a polar, protic solvent such as methyl alcohol to yield the4-aminopicolinate of Formula I-D, wherein Ar is as previously defined.The 4-aminopicolinate of Formula I-D can also be prepared starting fromthe 6-bromopicolinate, which can be synthesized as in Fields, S. C. etal. U.S. Pat. No. 6,297,197 B1, Oct. 2, 2001. In step f₂ of Scheme II,Suzuki coupling of the 6-bromopicolinate of Formula VIII with a boronicacid or ester, in the presence of a catalyst such asbis(triphenylphosphine)palladium(II) dichloride, cesium fluoride and apolar protic solvent mixture such as 1,2-dimethoxyethane-water at 110°C. in a microwave oven, provides the 4-aminopicolinate of Formula I-D,wherein Ar is as previously defined.

In step j of Scheme III, the 2-chloropyridin-3-ol of Formula IX can bebrominated with a brominating reagent such as N-bromosuccinimide in apolar, aprotic solvent such as acetonitrile to afford the4,6-dibromopyridin-3-ol of Formula X. The 4,6-dibromopyridin-3-ol ofFormula X can be transformed into the3-difluoromethoxy-4,6-dibromopyridine of Formula XI by reaction with2-chloro-2,2-difluoro-1-phenylethanone in the presence of a polar,aprotic solvent such as acetonitrile at 100° C. in a microwave reactoras in step k. In steps c₂ and d₂ of Scheme III, the 4-bromo group on thecompound of Formula XI can be displaced with sodium azide in a polar,aprotic solvent such as DMF at 65° C. The resulting 4-azido compound canbe reduced with sodium borohydride in a polar, protic solvent such asmethyl alcohol to give the 4-amino-6-bromopyridine of Formula XII. The4-amino-6-bromopyridine of Formula XII can be converted to the 6-arylpyridine of Formula XIII, wherein Ar is as previously defined, viaSuzuki coupling with a boronic acid or ester, in the presence of acatalyst such as bis(triphenylphosphine)palladium(II) dichloride, cesiumfluoride and a polar protic solvent mixture such as1,2-dimethoxyethane-water at 110° C. in a microwave reactor, as in stepf₃ of Scheme III. In step 1, the 6-aryl pyridine of Formula XIII can bereacted with carbon monoxide in the presence of a catalyst, such as[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), andtriethylamine in a polar, protic solvent such as ethyl alcohol at 105°C. in a bomb reactor to provide the 6-arylpicolinate of Formula I-E,wherein Ar is as previously defined.

In step m of Scheme IV, the 4,5,6-trichloropicolinate of Formula XIV canbe converted to the corresponding isopropyl ester of Formula XV, viareaction with isopropyl alcohol and concentrated sulfuric acid at refluxtemperature under Dean-Stark conditions. The isopropyl ester of FormulaXV can be reacted with a fluoride ion source such as cesium fluoride ina polar, aprotic solvent such as dimethyl sulfoxide at 80° C. underDean-Stark conditions to yield the isopropyl 4,5,6-trifluoropicolinateof Formula XVI, as in step n of Scheme IV. In step o, the isopropyl4,5,6-trifluoropicolinate of Formula XVI can be aminated with a nitrogensource such as ammonia in a polar, aprotic solvent such as dimethylsulfoxide to produce a 4-amino-5,6-difluoropicolinate of Formula XVII.The fluoro substituent in the 6-position of the4-amino-5,6-difluoropicolinate of Formula XVII can be exchanged with achloro substituent by treatment with a chloride source, such as hydrogenchloride in dioxane, in a Parr reactor at 100° C. to produce a4-amino-5-fluoro-6-chloro-picolinate of Formula XVIII, as in step p inScheme IV. In step q, the 4-amino-5-fluoro-6-chloropicolinate of FormulaXVIII is transesterified to the corresponding methyl ester of FormulaXIX by reaction with titanium(IV) isopropoxide in methyl alcohol atreflux temperature.

In step r₁ of Scheme V, the 4-amino-5-fluoro-6-chloropicolinate ofFormula XIX can be transformed into the3-iodo-4-amino-5-fluoro-6-chloropicolinate of Formula XX via reactionwith iodinating reagents such as periodic acid and iodine in a polar,protic solvent such as methyl alcohol at reflux temperature. The3-iodo-4-amino-5-fluoro-6-chloro-picolinate of Formula XX can be treatedwith cesium carbonate and a catalytic amount of both copper(I) iodideand 1,10-phenanthroline in the presence of a polar, protic solvent suchas methyl alcohol at 65° C. to provide a3-methoxy-4-amino-5-fluoro-6-chloropicolinic acid of Formula I-F, as instep s₁ of Scheme V. The resulting picolinic acid of Formula I-F can beconverted to the 3-methoxy-4-amino-5-fluoro-6-chloropicolinate ofFormula I-G using standard esterification conditions, such as bytreatment with hydrogen chloride (gas) and methyl alcohol at 50° C. Instep f₄ of Scheme V, Suzuki coupling of the3-methoxy-4-amino-5-fluoro-6-chloropicolinate of Formula I-G with aboronic acid or ester, in the presence of a catalyst such asbis(triphenylphosphine)-palladium(II) dichloride, potassium fluoride anda polar protic solvent mixture such as acetonitrile-water at 110° C. ina microwave oven, provides the 6-arylpicolinate of Formula I-H, whereinAr is as previously defined. In step u of Scheme V, Stille coupling ofthe 3-methoxy-4-amino-5-fluoro-6-chloropicolinate of Formula I-G with astannane, such as tributyl(vinyl)stannane, in the presence of a catalystsuch as bis(triphenylphosphine)-palladium(II) dichloride, in anon-reactive solvent such as 1,2-dichloroethane at 120° C. in amicrowave reactor, provides a 6-(substituted)picolinate of Formula I-I,wherein Y is alkyl, cycloalkyl, alkenyl, haloalkenyl and halocycloalkyl.

In step f₅ of Scheme VI, Suzuki coupling of the3-methoxy-4-amino-5-fluoro-6-chloropicolinate of Formula XIX, with aboronic acid or ester, in the presence of a catalyst such asbis(triphenylphosphine)palladium(II) dichloride, potassium fluoride anda polar protic solvent mixture such as acetonitrile-water at 115° C. ina microwave reactor, provides a 6-arylpicolinate of Formula XXI, whereinAr is as previously defined. In step r₂ of Scheme VI, the6-arylpicolinate of Formula XXI can be transformed into the3-iodo-6-arylpicolinate of Formula XXII via reaction with iodinatingreagents such as periodic acid and iodine in a polar, protic solventsuch as methyl alcohol at reflux temperature. The3-iodo-6-arylpicolinate of Formula XXII can be treated with cesiumcarbonate and a catalytic amount of both copper(I) iodide and1,10-phenanthroline in the presence of a polar, protic solvent such asmethyl alcohol at 70° C. to provide a 3-methoxy-6-arylpicolinic acid ofFormula I-J, as in step s₂ of Scheme VI.

In step v₁ of Scheme VII, a 3-iodo-4-amino-5-fluoro-6-arylpicolinate ofFormula XXII can be coupled with tributylmethylthiostannane, using apalladium catalyst such as his (triphenylphosphine) palladium (II)chloride in a polar solvent such as dimethylformamide at 100° C. toprovide 3-methylthio-4-amino-5-fluoro-6-arylpicolinates of FormulaXXIII, wherein Ar is as previously defined. Alternately, in step v₂ ofScheme VII, the 3-iodo-4-amino-5-fluoro-6-chloropicolinate of FormulaXX, can be coupled with tributylmethylthiostannane, using a palladiumcatalyst such as his (triphenylphosphine) palladium (II) chloride in apolar solvent such as dimethylformamide at 100° C., to provide the3-methylthio-4-amino-5-fluoro-6-chloro picolinate of Formula XXIV. Instep f₆ of Scheme VII, compounds of Formula XXIV can be reacted with aboronic acid or ester, in the presence of a catalyst such asbis(triphenylphosphine)palladium(II) dichloride, potassium fluoride anda polar protic solvent mixture such as acetonitrile-water at 115° C. ina microwave reactor to provide compounds of Formula XXIII

In step w₁ of Scheme VIII, the known methyl4-amino-6-bromo-3-methoxypicolinate of Formula VIII (prepared asdescribed in Fields, S. C. et al. WO 2001051468) can be converted to the6-vinylpicolinate of Formula XXV via a Stille coupling usingvinyltributyltin and a palladium catalyst such asbis(triphenylphosphine)palladium (II) dichloride in a solvent likedichloroethane. In step x₁, the amino group can be protected as abis(tert-butyl carbamate) group in the 6-vinylpicolinate of Formula XXVIin the presence of a catalytic amount of 4-(dimethylamino)pyridine in asolvent like dichloroethane. In step y, the vinyl group can be convertedto an aldehyde group via ozonolyzis in a solvent such as dichloromethaneand in the presence of a reducing agent like triphenylphosphine toafford the 6-formylpicolinate of Formula XXVII. In step z, the6-(difluoromethyl)picolinate of Formula XXVIII can be prepared by aone-pot, two step reaction sequence using firstbis(2-methoxyethyl)aminosulfur trifluoride (deoxo-fluor) to convert thealdehyde group to the difluoromethyl group in a solvent likedichloromethane, followed by deprotection of the carbamate groups usingtrifluoro acetic acid.

In step w₂ of Scheme IX, methyl 4-amino-6-bromo-3-methoxypicolinate ofFormula VIII can be converted to the 6-(1-ethoxyvinyl)picolinate ofFormula XXIX via a Stille coupling using (1-ethoxyvinyl)tributyltin anda palladium catalyst such as bis(triphenylphosphine)palladium (II)dichloride in a solvent like dichloroethane. In step aa, the6-acetylpicolinate of Formula XXX can be prepared by treatment of the6-(1-ethoxyvinyl)picolinate of Formula XXIX with a 2N aqueous solutionof hydrochloric acid in a solvent like tetrahydrofuran. In step bb, theketone group can be reduced to the alcohol group in the(1-hydroxyethyl)picolinate of Formula XXXI, by using a reducing agentlike sodium borohydride in a solvent like methanol. In step cc, thefluoro group in the 6-(1-fluoroethyl)picolinate of Formula XXXII can beintroduced using deoxo-fluor in a solvent like dichoromethane. The6-(1-fluoroethyl)picolinic acid of Formula XXXIII can be obtained bydeesterification of the methyl ester group, as in step dd, using a 2Naqueous solution of sodium hydroxide in a mixture of solvent liketetrahydrofuran and methanol. In step x₂, the amino group can beprotected as a bis(tert-butyl carbamate) group in the 6-acetylpicolinateof Formula XXXIV in the presence of a catalytic amount of4-(dimethylamino)pyridine in a solvent like dichloroethane. In step ee,the 6-(1,1-difluoroethyl)picolinate of Formula XXXV can be prepared by aone-pot, two step reaction sequence using first deoxo-fluor to convertthe methyl ketone group to the difluoroethyl group in a solvent likedichloromethane, followed by deprotection of the carbamate groups usingtrifluoro acetic acid. The acid can be formed as in step dd.

In step ff of Scheme X, the compound of Formula XXXVI, where Ar is aspreviously defined, X is chloro or bromo and R₁₁ is an acid derivative(synthesized as in Renga, J. M. et al. U.S. Patent applications20100311981 and 20100311594), can be transformed via reaction with analkoxy, haloalkoxy, alkylthio, haloalkylthio neat or in a polar aproticsolvent such as THF or DMSO to afford the compound of Formula XXXVII,wherein Ar and R₁₁ are as previously defined, and Q is alkoxy,haloalkoxy, alkylthio, haloalkylthio.

In step gg of Scheme XI, the compound of Formula XXXVI can be convertedto a compound of Formula XXXVIII using reagents such as methylamine ordimethylamine, depending on the level of substitution desired.

In step hh of Scheme XII, compounds of Formula XXXVI can be converted toa mixture of picolinate regioisomers of Formula XXXIX and XXXX(XXXIX/XXXX 4:1) via addition of 2,2,2-trifluoroethanethiol in thepresence of a base like potassium carbonate.

The compounds of described herein, obtained by any of these processes,can be recovered by conventional means. Typically, the reaction mixtureis acidified with an aqueous acid, such as hydrochloric acid, andextracted with an organic solvent, such as ethyl acetate ordichloromethane. The organic solvent and other volatiles can be removedby distillation or evaporation to obtain the desired compound of FormulaA, which can be purified by standard procedures, such as byrecrystallization or chromatography.

The compounds described herein have been found to be useful aspre-emergence and post-emergence herbicides. They can be employed atnon-selective (higher) rates of application to control a broad spectrumof the vegetation in an area or at lower rates of application for theselective control of undesirable vegetation. Areas of applicationinclude pasture and rangelands, roadsides and rights-of-way, power linesand any industrial areas where control of undesirable vegetation isdesirable. Another use is the control of unwanted vegetation in cropssuch as corn, rice and cereals. They can also be used to controlundesirable vegetation in tree crops such as citrus, apple, rubber, oilpalm, forestry and others. It is usually preferred to employ thecompounds post-emergence. It is further usually preferred to use thecompounds to control a wide spectrum of woody plants, broadleaf andgrass weeds, and sedges.

Use of the compounds to control undesirable vegetation in establishedcrops is especially indicated. While each of the compounds encompassedby Formula A is within the scope of the invention, the degree ofherbicidal activity, the crop selectivity, and the spectrum of weedcontrol obtained varies depending upon the substituents present. Anappropriate compound for any specific herbicidal utility can beidentified by using the information presented herein and routinetesting.

The term herbicide is used herein to mean an active ingredient thatkills, controls or otherwise adversely modifies the growth of plants. Anherbicidally effective or vegetation controlling amount is an amount ofactive ingredient which causes an adversely modifying effect andincludes deviations from natural development, killing, regulation,desiccation, retardation, and the like. The terms plants and vegetationinclude germinant seeds, emerging seedlings, above and below groundplant parts such as shoots, roots, tubers, rhizomes and the like, andestablished vegetation.

Herbicidal activity is exhibited by the compounds of the presentinvention when they are applied directly to the plant or to the locus ofthe plant, to the soil, or to the flood or irrigation water at any stageof growth or before planting or emergence. The effect observed dependsupon the plant species to be controlled, the stage of growth of theplant, the application parameters of dilution and spray drop size, theparticle size of solid components, the environmental conditions at thetime of use, the specific compound employed, the specific adjuvants andcarriers employed, the soil type, the water quality, and the like, aswell as the amount of chemical applied. These and other factors can beadjusted as is known in the art to promote non-selective or selectiveherbicidal action. Generally, it is preferred to apply the compounds ofdescribed herein post-emergence to relatively immature undesirablevegetation to achieve the maximum control of weeds.

Application rates of about 1 to about 4,000 grams/hectare (g/ha) aregenerally employed in post-emergence operations; for pre-emergenceapplications, rates of about 1 to about 4,000 g/ha are generallyemployed. The higher rates designated generally give non-selectivecontrol of a broad variety of undesirable vegetation. The lower ratestypically give selective control and can be employed in the locus ofcrops.

The herbicidal compounds of the present invention are often applied inconjunction with one or more other herbicides to control a wider varietyof undesirable vegetation. When used in conjunction with otherherbicides, the presently claimed compounds can be formulated with theother herbicide or herbicides, tank mixed with the other herbicide orherbicides or applied sequentially with the other herbicide orherbicides. Some of the herbicides that can be employed in conjunctionwith the compounds of the present invention include: 4-CPA; 4-CPB;4-CPP; 2,4-D; 3,4-DA; 2,4-DB; 3,4-DB; 2,4-DEB; 2,4-DEP; 3,4-DP;2,3,6-TBA; 2,4,5-T; 2,4,5-TB; acetochlor, acifluorfen, aclonifen,acrolein, alachlor, allidochlor, alloxydim, allyl alcohol, alorac,ametridione, ametryn, amibuzin, amicarbazone, amidosulfuron,aminocyclopyrachlor, aminopyralid, amiprofos-methyl, amitrole, ammoniumsulfamate, anilofos, anisuron, asulam, atraton, atrazine, azafenidin,azimsulfuron, aziprotryne, barban, BCPC, beflubutamid, benazolin,bencarbazone, benfluralin, benfuresate, bensulfuron, bensulide,bentazone, benzadox, benzfendizone, benzipram, benzobicyclon,benzofenap, benzofluor, benzoylprop, benzthiazuron, bicyclopyrone,bifenox, bilanafos, bispyribac, borax, bromacil, bromobonil,bromobutide, bromofenoxim, bromoxynil, brompyrazon, butachlor,butafenacil, butamifos, butenachlor, buthidazole, buthiuron, butralin,butroxydim, buturon, butylate, cacodylic acid, cafenstrole, calciumchlorate, calcium cyanamide, cambendichlor, carbasulam, carbetamide,carboxazole chlorprocarb, carfentrazone, CDEA, CEPC, chlomethoxyfen,chloramben, chloranocryl, chlorazifop, chlorazine, chlorbromuron,chlorbufam, chloreturon, chlorfenac, chlorfenprop, chlorflurazole,chlorflurenol, chloridazon, chlorimuron, chlomitrofen, chloropon,chlorotoluron, chloroxuron, chloroxynil, chlorpropham, chlorsulfuron,chlorthal, chlorthiamid, cinidon-ethyl, cinmethylin, cinosulfuron,cisanilide, clethodim, cliodinate, clodinafop, clofop, clomazone,clomeprop, cloprop, cloproxydim, clopyralid, cloransulam, CMA, coppersulfate, CPMF, CPPC, credazine, cresol, cumyluron, cyanatryn, cyanazine,cycloate, cyclosulfamuron, cycloxydim, cycluron, cyhalofop, cyperquat,cyprazine, cyprazole, cypromid, daimuron, dalapon, dazomet, delachlor,desmedipham, desmetryn, di-allate, dicamba, dichlobenil, dichloralurea,dichlormate, dichlorprop, dichlorprop-P, diclofop, diclosulam,diethamquat, diethatyl, difenopenten, difenoxuron, difenzoquat,diflufenican, diflufenzopyr, dimefuron, dimepiperate, dimethachlor,dimethametryn, dimethenamid, dimethenamid-P, dimexano, dimidazon,dinitramine, dinofenate, dinoprop, dinosam, dinoseb, dinoterb,diphenamid, dipropetryn, diquat, disul, dithiopyr, diuron, DMPA, DNOC,DSMA, EBEP, eglinazine, endothal, epronaz, EPTC, erbon, esprocarb,ethalfluralin, ethametsulfuron, ethidimuron, ethiolate, ethofumesate,ethoxyfen, ethoxysulfuron, etinofen, etnipromid, etobenzanid, EXD,fenasulam, fenoprop, fenoxaprop, fenoxaprop-P, fenoxasulfone,fenteracol, fenthiaprop, fentrazamide, fenuron, ferrous sulfate,flamprop, flamprop-M, flazasulfuron, florasulam, fluazifop, fluazifop-P,fluazolate, flucarbazone, flucetosulfuron, fluchloralin, flufenacet,flufenican, flufenpyr, flumetsulam, flumezin, flumiclorac, flumioxazin,flumipropyn, fluometuron, fluorodifen, fluoroglycofen, fluoromidine,fluoronitrofen, fluothiuron, flupoxam, flupropacil, flupropanate,flupyrsulfuron, fluridone, flurochloridone, fluroxypyr, flurtamone,fluthiacet, fomesafen, foramsulfuron, fosamine, furyloxyfen,glufosinate, glufosinate-P, glyphosate, halosafen, halosulfuron,haloxydine, haloxyfop, haloxyfop-P, hexachloroacetone, hexaflurate,hexazinone, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin,imazethapyr, imazosulfuron, indanofan, indaziflam, iodobonil,iodomethane, iodosulfuron, ioxynil, ipazine, ipfencarbazone, iprymidam,isocarbamid, isocil, isomethiozin, isonoruron, isopolinate, isopropalin,isoproturon, isouron, isoxaben, isoxachlortole, isoxaflutole,isoxapyrifop, karbutilate, ketospiradox, lactofen, lenacil, linuron,MAA, MAMA, MCPA, MCPA-thioethyl, MCPB, mecoprop, mecoprop-P, medinoterb,mefenacet, mefluidide, mesoprazine, mesosulfuron, mesotrione, metam,metamifop, metamitron, metazachlor, metazosulfuron, metflurazon,methabenzthiazuron, methalpropalin, methazole, methiobencarb,methiozolin, methiuron, methometon, methoprotryne, methyl bromide,methyl isothiocyanate, methyldymron, metobenzuron, metobromuron,metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, molinate,monalide, monisouron, monochloroacetic acid, monolinuron, monuron,morfamquat, MSMA, naproanilide, napropamide, naptalam, neburon,nicosulfuron, nipyraclofen, nitralin, nitrofen, nitrofluorfen,norflurazon, noruron, OCH, orbencarb, ortho-dichlorobenzene,orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxapyrazon,oxasulfuron, oxaziclomefone, oxyfluorfen, parafluron, paraquat,pebulate, pelargonic acid, pendimethalin, penoxsulam, pentachlorophenol,pentanochlor, pentoxazone, perfluidone, pethoxamid, phenisopham,phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercury acetate,picloram, picolinafen, pinoxaden, piperophos, potassium arsenite,potassium azide, potassium cyanate, pretilachlor, primisulfuron,procyazine, prodiamine, profluazol, profluralin, profoxydim,proglinazine, prometon, prometryn, propachlor, propanil, propaquizafop,propazine, propham, propisochlor, propoxycarbazone, propyrisulfuron,propyzamide, prosulfalin, prosulfocarb, prosulfuron, proxan, prynachlor,pydanon, pyraclonil, pyraflufen, pyrasulfotole, pyrazolynate,pyrazosulfuron, pyrazoxyfen, pyribenzoxim, pyributicarb, pyriclor,pyridafol, pyridate, pyriftalid, pyriminobac, pyrimisulfan, pyrithiobac,pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine,quinonamid, quizalofop, quizalofop-P, rhodethanil, rimsulfuron,saflufenacil, S-metolachlor, sebuthylazine, secbumeton, sethoxydim,siduron, simazine, simeton, simetryn, SMA, sodium arsenite, sodiumazide, sodium chlorate, sulcotrione, sulfallate, sulfentrazone,sulfometuron, sulfosulfuron, sulfuric acid, sulglycapin, swep, TCA,tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim,terbacil, terbucarb, terbuchlor, terbumeton, terbuthylazine, terbutryn,tetrafluron, thenylchlor, thiazafluron, thiazopyr, thidiazimin,thidiazuron, thiencarbazone-methyl, thifensulfuron, thiobencarb,tiocarbazil, tioclorim, topramezone, tralkoxydim, triafamone,tri-allate, triasulfuron, triaziflam, tribenuron, tricamba, triclopyr,tridiphane, trietazine, trifloxysulfuron, trifluralin, triflusulfuron,trifop, trifopsime, trihydroxytriazine, trimeturon, tripropindan,tritac, tritosulfuron, vernolate and xylachlor.

The compounds of the present invention can generally be employed incombination with known herbicide safeners, such as benoxacor,benthiocarb, brassinolide, cloquintocet (mexyl), cyometrinil, daimuron,dichlormid, dicyclonon, dimepiperate, disulfoton, fenchlorazole-ethyl,fenclorim, flurazole, fluxofenim, furilazole, harpin proteins,isoxadifen-ethyl, mefenpyr-diethyl, MG 191, MON 4660, naphthalicanhydride (NA), oxabetrinil, R29148 and N-phenylsulfonylbenzoic acidamides, to enhance their selectivity.

The compounds of the present invention can additionally be employed tocontrol undesirable vegetation in many crops that have been madetolerant to or resistant to them or to other herbicides by geneticmanipulation or by mutation and selection. The herbicidal compounds ofthe present invention can, further, be used in conjunction withglyphosate, glufosinate, dicamba, imidazolinones or 2,4-D onglyphosate-tolerant, glufosinate-tolerant, dicamba-tolerant,imidazolinone-tolerant or 2,4-D-tolerant crops. It is generallypreferred to use the compounds of the invention in combination withherbicides that are selective for the crop being treated and whichcomplement the spectrum of weeds controlled by these compounds at theapplication rate employed. It is further generally preferred to applythe compounds of the invention and other complementary herbicides at thesame time, either as a combination formulation or as a tank mix.Similarly, the herbicidal compounds of the present invention can be usedin conjunction with acetolactate synthase inhibitors on acetolactatesynthase inhibitor tolerant crops or4-hydroxyphenyl-pyruvate-dioxygenase inhibitors onhydroxyphenyl-pyruvate-dioxygenase tolerant crops.

While it is possible to utilize the compounds described herein, e.g.,3-alkoxy, thioalkyl and amino-4-amino-6-(substituted)picolinatecompounds of Formula A directly as herbicides, it is preferable to usethem in mixtures containing an herbicidally effective amount of thecompound along with at least one agriculturally acceptable adjuvant orcarrier. Suitable adjuvants or carriers should not be phytotoxic tovaluable crops, particularly at the concentrations employed in applyingthe compositions for selective weed control in the presence of crops,and should not react chemically with the compounds described herein orother composition ingredients. Such mixtures can be designed forapplication directly to weeds or their locus or can be concentrates orformulations that are normally diluted with additional carriers andadjuvants before application. They can be solids, such as, for example,dusts, granules, water dispersible granules, or wettable powders, orliquids, such as, for example, emulsifiable concentrates, solutions,emulsions or suspensions. They can also be provided as a pre-mix or tankmixed.

Suitable agricultural adjuvants and carriers that are useful inpreparing the herbicidal mixtures of the invention are well known tothose skilled in the art. Some of these adjuvants include, but are notlimited to, crop oil concentrate (mineral oil (85%)+emulsifiers (15%));nonylphenol ethoxylate; benzylcocoalkyldimethyl quaternary ammoniumsalt; blend of petroleum hydrocarbon, alkyl esters, organic acid, andanionic surfactant; C₉-C₁₁ alkylpolyglycoside; phosphated alcoholethoxylate; natural primary alcohol (C₁₂-C₁₆) ethoxylate;di-sec-butylphenol EO-PO block copolymer; polysiloxane-methyl cap;nonylphenol ethoxylate+urea ammonium nitrrate; emulsified methylatedseed oil; tridecyl alcohol (synthetic) ethoxylate (8EO); tallow amineethoxylate (15 EO); PEG(400) dioleate-99.

Liquid carriers that can be employed include water and organic solvents.The organic solvents typically used include, but are not limited to,petroleum fractions or hydrocarbons such as mineral oil, aromaticsolvents, paraffinic oils, and the like; vegetable oils such as soybeanoil, rapeseed oil, olive oil, castor oil, sunflower seed oil, coconutoil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil,safflower oil, sesame oil, tung oil and the like; esters of the abovevegetable oils; esters of monoalcohols or dihydric, trihydric, or otherlower polyalcohols (4-6 hydroxy containing), such as 2-ethylhexylstearate, n-butyl oleate, isopropyl myristate, propylene glycoldioleate, di-octyl succinate, di-butyl adipate, di-octyl phthalate andthe like; esters of mono-, di- and poly-carboxylic acids and the like.Specific organic solvents include toluene, xylene, petroleum naphtha,crop oil, acetone, methyl ethyl ketone, cyclohexanone,trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butylacetate, propylene glycol monomethyl ether and diethylene glycolmonomethyl ether, methyl alcohol, ethyl alcohol, isopropyl alcohol, amylalcohol, ethylene glycol, propylene glycol, glycerine,N-methyl-2-pyrrolidinone, N,N-dimethyl alkylamides, dimethyl sulfoxide,liquid fertilizers, and the like. Water is generally the carrier ofchoice for the dilution of concentrates.

Suitable solid carriers include talc, pyrophyllite clay, silica,attapulgus clay, kaolin clay, kieselguhr, chalk, diatomaceous earth,lime, calcium carbonate, bentonite clay, Fuller's earth, cottonseedhulls, wheat flour, soybean flour, pumice, wood flour, walnut shellflour, lignin, and the like.

It is usually desirable to incorporate one or more surface-active agentsinto the compositions of the present invention. Such surface-activeagents are advantageously employed in both solid and liquidcompositions, especially those designed to be diluted with carrierbefore application. The surface-active agents can be anionic, cationicor nonionic in character and can be employed as emulsifying agents,wetting agents, suspending agents, or for other purposes. Surfactantsconventionally used in the art of formulation and which may also be usedin the present formulations are described, inter alia, in McCutcheon'sDetergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood, N.J.,1998, and in Encyclopedia of Surfactants, Vol. I-III, ChemicalPublishing Co., New York, 1980-81. Typical surface-active agents includesalts of alkyl sulfates, such as diethanolammonium lauryl sulfate;alkylarylsulfonate salts, such as calcium dodecylbenzenesulfonate;alkylphenol-alkylene oxide addition products, such as nonylphenol-C₁₈ethoxylate; alcohol-alkylene oxide addition products, such as tridecylalcohol-C₁₆ ethoxylate; soaps, such as sodium stearate;alkylnaphthalene-sulfonate salts, such as sodiumdibutyl-naphthalenesulfonate; dialkyl esters of sulfosuccinate salts,such as sodium di(2-ethylhexyl) sulfosuccinate; sorbitol esters, such assorbitol oleate; quaternary amines, such as lauryl trimethylammoniumchloride; polyethylene glycol esters of fatty acids, such aspolyethylene glycol stearate; block copolymers of ethylene oxide andpropylene oxide; salts of mono- and dialkyl phosphate esters; vegetableor seed oils such as soybean oil, rapeseed/canola oil, olive oil, castoroil, sunflower seed oil, coconut oil, corn oil, cottonseed oil, linseedoil, palm oil, peanut oil, safflower oil, sesame oil, tung oil and thelike; and esters of the above vegetable oils, particularly methylesters.

Oftentimes, some of these materials, such as vegetable or seed oils andtheir esters, can be used interchangeably as an agricultural adjuvant,as a liquid carrier or as a surface active agent.

Other adjuvants commonly used in agricultural compositions includecompatibilizing agents, antifoam agents, sequestering agents,neutralizing agents and buffers, corrosion inhibitors, dyes, odorants,spreading agents, penetration aids, sticking agents, dispersing agents,thickening agents, freezing point depressants, antimicrobial agents, andthe like. The compositions may also contain other compatible components,for example, other herbicides, plant growth regulants, fungicides,insecticides, and the like and can be formulated with liquid fertilizersor solid, particulate fertilizer carriers such as ammonium nitrate, ureaand the like.

The concentration of the active ingredients in the herbicidalcompositions of this invention is generally from about 0.001 to about 98percent by weight. Concentrations from about 0.01 to about 90 percent byweight are often employed. In compositions designed to be employed asconcentrates, the active ingredient is generally present in aconcentration from about 5 to about 98 weight percent, preferably about10 to about 90 weight percent. Such compositions are typically dilutedwith an inert carrier, such as water, before application. The dilutedcompositions usually applied to weeds or the locus of weeds generallycontain about 0.0001 to about 1 weight percent active ingredient andpreferably contain about 0.001 to about 0.05 weight percent.

The present compositions can be applied to weeds or their locus by theuse of conventional ground or aerial dusters, sprayers, and granuleapplicators, by addition to irrigation or flood water, and by otherconventional means known to those skilled in the art.

The following Examples are presented to illustrate the various aspectsof this invention and should not be construed as limitations to theclaims.

EXAMPLES

General Considerations: Fluorine spectra were acquired at 376 MHz on aBruker DRX400 spectrometer. The spectra were referenced totrichlorofluoromethane (CFCl₃) as an external standard and weretypically conducted with proton decoupling.

Example 1 Preparation of (4-bromo-2-fluorophenyl)trimethylsilane

A solution of n-butyllithium (n-BuLi, 2.5 Molar (M) in hexanes; 900microliters (μL), 2.2 millimoles (mmol), 1.1 equivalents (equiv)) wasadded to a stirred solution of 1,4-dibromo-2-fluorobenzene (500milligrams (mg), 2.0 mmol, 1.0 equiv) in diethyl ether (Et₂O; 10milliliters (mL)) at −78° C. The resulting pale yellow solution wasstirred at −78° C. for 2 hours (h). Chlorotrimethylsilane (TMSCl; 300μL, 2.4 mmol, 1.2 equiv) was added, and the resulting pale yellowsolution was allowed to slowly warm to 23° C., by allowing the dryice/acetone bath to melt, and was stirred for 72 h. The reaction mixturewas diluted with water (H₂O; 50 mL) and was extracted withdichloromethane (CH₂Cl₂; 3×50 mL). The combined organic layers weredried over magnesium sulfate (MgSO₄), gravity filtered, and concentratedby rotary evaporation to afford the title compound as a pale yellow oil(350 mg, 71%): IR (thin film) 3068 (w), 2955 (m), 2927 (m), 2855 (w),1598 (w), 1567 (w) cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 7.38-7.49 (m, 3H),0.30 (s, 9H).

Example 2 Preparation of (4-bromo-2,3-difluorophenyl)trimethylsilane

Diisopropylamine (7.86 grams (g), 78 mmol) was dissolved intetrahydrofuran (THF; 104 mL) and cooled to −75° C. utilizing a dryice/acetone bath. A solution of n-BuLi (2.5 M in hexanes; 22.80 mL, 57.0mmol) was added dropwise, and the solution was again cooled to −75° C.1-Bromo-2,3-difluorobenzene (10 g, 51.8 mmol) was dissolved in THF (25.9mL), and the solution was added dropwise keeping the temperature below−60° C. The reaction mixture was then allowed to warm to −15° C. beforecooling again to −75° C. TMSCl (7.29 mL, 57.0 mmol) was then addeddropwise, and the reaction mixture was allowed to warm to 25° C. andthen concentrated under vacuum. The residue was partitioned betweenethyl acetate (EtOAc) and H₂O. The organic phase was washed twice morewith H₂O and concentrated. Kugelrohr distillation at 88° C. provided theproduct in greater purity but an impurity was distilling at thattemperature. Kugelrohr distillation of that purified distillate at 75°C. led to purer product but some product was left in the pot. Thisprocess yielded the title compound as a clear oil (3.0 g, 21.83%, 90%purity): ¹H NMR (300 MHz, CDCl₃) δ 7.28 (ddd, J=7.8, 5.2, 1.3 Hz, 1H),6.98 (ddd, J=8.0, 4.8, 1.9 Hz, 1H), 0.32 (s, 9H); EIMS m/z 264, 266.

Example 3 Preparation of (4-bromo-2,5-difluorophenyl)trimethylsilane

To a solution of 1,4-dibromo-2,5-difluorobenzene (5 g, 18.4 mmol) inanhydrous Et₂O (60 mL) at −78° C. (dry ice/acetone bath) was addedn-BuLi (7.72 mL, 19.31 mmol) dropwise. The reaction mixture was stirredat −78° C. for 30 minutes (min) (light yellow color), then TMSCl (2.59mL, 20.23 mmol) was added. The reaction mixture was allowed to slowlywarm to 20° C. and was stirred for 12 h. The reaction mixture was pouredinto a saturated (satd) aqueous (aq) ammonium chloride solution (NH₄Cl;150 mL), and the crude product was extracted with Et₂O (3×). Thecombined organic layers were washed with satd aq NaCl, dried over MgSO₄,filtered and concentrated (orange/brown oil). The residue was purifiedby column chromatography (silica gel (SiO₂), eluting with hexanes) toafford the title compound as a colorless oil (4.17 g, 86%): ¹H NMR (400MHz, CDCl₃) δ 7.20 (dd, J=7.1, 5.1 Hz, 1H), 7.09 (dd, J=8.0, 4.4 Hz,1H), 0.31 (d, J=0.9 Hz, 9H); ¹⁹F NMR (376 MHz, CDCl₃) δ −105.42,−115.48; EIMS m/z 266.

Example 4 Preparation of(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)trimethylsilane

A solution of n-BuLi (2.5 M in hexanes; 8.5 mL, 21 mmol, 1.1 equiv) wasadded to a stirred solution of (4-bromo-2-fluorophenyl)trimethylsilane(4.8 g, 19 mmol, 1.0 equiv) in THF (80 mL) at −78° C. The resultingorange solution was stirred at −78° C. for 15 min.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.4 mL, 21 mmol,1.1 equiv) was added, and the cloudy orange solution was allowed toslowly warm to 23° C., by allowing the dry ice/acetone bath to melt, andwas stirred for 20 h. The reaction mixture was diluted with H₂O (200mL), adjusted to approximately pH=4 using 1 M hydrochloric acid (HCl),and extracted with CH₂Cl₂ (3×100 mL). The combined organic layers weredried (MgSO₄), gravity filtered, and concentrated by rotary evaporationto afford the crude product,(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane,as a pale yellow semisolid (6.0 g, 99% crude yield): ¹H NMR (400 MHz,CDCl₃) δ 7.55 (dt, J=7.5, 1 Hz, 1H), 7.38-7.42 (m, 2H), 1.34 (s, 12H),0.29 (d, J=1 Hz, 9H).

Example 5 Preparation of(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)trimethylsilane

To a −78° C. solution of 1,4-dibromo-2-fluorobenzene (4 g, 15.75 mmol)in THF (52.5 mL) was added a solution of n-BuLi (2.5 M in hexanes; 6.3mL, 15.75 mmol). The reaction mixture was stirred at −78° C. for 30 min2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.21 mL, 15.75mmol) was then added, and the mixture was stirred at −78° C. for anadditional 1 h. A solution of n-BuLi (2.5 M in hexanes; 6.3 mL, 15.75mmol) was then added, followed after 30 min by TMSCl (4.03 mL, 31.5mmol). The reaction mixture was allowed to warm slowly to roomtemperature and was stirred overnight. The mixture was then poured intoa half saturated NH₄Cl solution (300 mL), and the crude product wasextracted with Et₂O (3×). The combined organic layers were dried overMgSO₄, filtered, concentrated and dried in vacuo to afford the titlecompound as a yellow oil (4.87 g, 11.92 mmol, 76% yield based on a 72%purity): ¹H NMR (400 MHz, CDCl₃) δ 7.71 (dd, J=7.2, 6.0 Hz, 1H), 7.26(dt, J=7.2, 1.2 Hz, 1H), 7.16 (dd, J=9.6, 0.4 Hz, 1H), 1.36 (s, 12H),0.26 (s, 9H); ¹⁹F NMR (376 MHz, CDCl₃) δ −104.02; EIMS m/z 294.

Example 6 Preparation of(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane

A solution of sec-butyllithium (1.4 M in cyclohexane; 19.17 mL, 26.8mmol) was added to THF (53.7 mL) cooled to −75° C. To this solution wasadded (2,3-difluorophenyl)-trimethylsilane (prepared as in Heiss, C. etal. Eur. J. Org. Chem. 2007, 4, 669-675; 5.0 g, 26.8 mmol) dropwisekeeping the temperature below −70° C. The resulting reaction mixture wasstirred at −75° C. for 45 min after which time2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.49 g, 29.5 mmol)was added dropwise keeping the temperature below −70° C. The reactionmixture was then allowed to warm to 25° C. and was partitioned betweenEt₂O and H₂O. The aqueous phase was acidified to pH 3 with 12 Normal (N)HCl. The product was extracted with Et₂O, and the organic phase wasdried and concentrated under vacuum to provide the title compound as awhite solid (5.03 g, 60%): ¹H NMR (300 MHz, CDCl₃) δ 7.42 (ddd, J=7.3,4.4, 0.7 Hz, 1H), 7.09 (ddd, J=7.3, 4.1, 0.9 Hz, 1H), 1.36 (s, 12H),0.32 (d, J=0.9 Hz, 9H); EIMS m/z 312.

Example 7 Preparation of(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane

A mixture of (4-bromo-2,5-difluorophenyl)trimethylsilane (10 g, 37.7mmol), potassium acetate (11.10 g, 113 mmol),1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II)dichloromethane complex (2.76 g, 3.77 mmol), and bis(pinacolato)diboron(10.53 g, 41.5 mmol) in dimethyl sulfoxide (DMSO; 126 mL) was stirred at80° C. for 12 h. The mixture was poured into H₂O (600 mL), and the crudeproduct was extracted with Et₂O (3×). The combined organic layers weredried over MgSO₄, filtered and concentrated to give a black oil. Theresidue was filtered through a short pad of silica gel and washed withEt₂O. After concentration, the title compound was obtained as anorange-brown oil (12.14 g, 31.9 mmol, 85% yield based on an 82% purity),which was used without further purification in the next step: ¹H NMR(400 MHz, CDCl₃) δ 7.30 (dd, J=7.8, 4.1 Hz, 1H), 7.00 (dd, J=8.4, 3.7Hz, 1H), 1.35 (s, 12H), 0.30 (d, J=0.9 Hz, 9H); ¹⁹F NMR (376 MHz, CDCl₃)δ −109.11, −110.92; ELMS m/z 312.

Example 8 Preparation of methyl 4,6-dichloro-3-methoxypicolinate

Methyl 6-chloro-3-methoxypicolinate (prepared as in Van Heertum, J. C.et al. U.S. Pat. No. 5,571,775 A, Nov. 5, 1996; 4.0 g, 20 mmol) wasdissolved in dry CH₂Cl₂ (20 mL), treated with urea hydrogen peroxidecomplex (4.0 g, 43 mmol), cooled to 0-5° C., stirred and treated inportions with trifluoroacetic anhydride (5.6 mL, 40 mmol). The mixturewas allowed to warm to 20° C. and stirred for 20 h. An additionalportion of the urea hydrogen peroxide complex (2.0 g) andtrifluoroacetic anhydride (2.8 mL) were added and stirring was continuedfor 4 h. The mixture was stirred with 10% sodium bisulfite (NaHSO₃)solution until negative to starch-iodide paper. The organic phase waswashed with H₂O (10 mL), dried (Na₂SO₄) and evaporated. This materialwas dissolved in phosphorus oxychloride (POCl₃; 30 mL) and heated at 70°C. for 2 h and then at reflux for 3 h to produce a 1:1 mixture of theisomeric 4,5- and 4,6-dichloropicolinates. After cooling, the volatileswere removed under vacuum, the residue was combined with ice and theproduct was taken up in EtOAc. This solution was washed with H₂O, dried(Na₂SO₄) and evaporated. The crude mixture was purified by reverse-phasehigh performance liquid chromatography (RP-HPLC; eluting with 60%acetonitrile (CH₃CN)—H₂O) to provide the title compound (1.1 g, 23%): ¹HNMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); EIMSm/z 235.

Example 9 Preparation of methyl 4-amino-6-chloro-3-methoxypicolinate(Compound 1)

Methyl 4,6-dichloro-3-methoxypicolinate (320 mg, 1.4 mmol) was dissolvedin dry N,N-dimethylformamide (DMF; 5 mL), treated with sodium azide (130mg, 2.0 mmol) and heated at 50° C. for 5 h. After cooling, the mixturewas shaken with EtOAc (20 mL) and H₂O (10 mL). The organic phase waswashed with H₂O (2×10 mL) and satd aq NaCl (1×10 mL), dried (Na₂SO₄) andevaporated. This material was dissolved in methyl alcohol (CH₃OH; 15mL), treated with sodium borohydride (NaBH₄; 55 mg, 1.4 mmol) andstirred at 20° C. for 1 h. The mixture was treated with H₂O (10 mL), andthe volatiles were removed under vacuum. The residue was taken up inEtOAc (25 mL), washed with H₂O (10 mL) and satd aq sodium chloride(NaCl; 10 mL), dried (Na₂SO₄), and evaporated to give the desiredproduct as a white solid (100 mg, 33%): mp 78-79° C.; ¹H NMR (400 MHz,CDCl₃) δ 6.76 (s, 1H), 4.84 (s, 2H), 3.95 (s, 3H), 3.87 (s, 3H); EIMSm/z 216.

Example 10 Preparation of methyl4-amino-5,6-dichloro-3-methoxypicolinate (Compound 2)

Methyl 4-amino-6-chloro-3-methoxypicolinate (260 mg, 1.2 mmol) wasdissolved in dry CH₃CN (7 mL), treated with sulfuryl chloride (120 μL,1.5 mmol) and stirred for 30 min. The solution was stirred with satd aqsodium bicarbonate (NaHCO₃; 10 mL) for 20 min and then mixed with EtOAc(20 mL) and satd aq NaCl (10 mL). The aqueous phase was extracted withEtOAc (15 mL), and the combined organic phases were washed with satd aqNaCl (10 mL), dried (Na₂SO₄) and evaporated to give the title compoundas a white solid (240 mg, 80%): mp 119-121° C.; ¹H NMR (400 MHz, CDCl₃)δ 5.04 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H); EIMS m/z 250.

Example 11 Preparation of methyl4-acetamido-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-hydroxypicolinate

Methyl 4-acetamido-3-(benzyloxy)-6-bromopicolinate (prepared as in Kong,L. C. C. et al. U.S. Patent Application Publication 2005/0176767; 1.5 g,4.0 mmol), (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (1.2 g, 5.9mmol), bis(triphenylphosphine)-palladium(II) dichloride (PdCl₂(PPh₃)₂;278 mg, 0.4 mmol), cesium fluoride (CsF; 1.2 g, 7.9 mmol),1,2-dimethoxyethane (DME; 7 mL), and H₂O (7 mL) were combined and heatedin a Biotage microwave at 100° C. for 15 min. H₂O was added to thereaction mixture, and the product was extracted with EtOAc. The combinedorganic extracts were washed with satd aq NaCl, dried with sodiumsulfate (Na₂SO₄), filtered and concentrated. Flash chromatography (SiO₂;0-45% EtOAc/cyclohexane gradient) afforded methyl4-acetamido-3-(benzyloxy)-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinateas a yellow solid: mp 115-120° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.87 (d,J=1.6 Hz, 1H), 7.66 (s, 1H), 7.59 (dd, J=8.5, 7.7 Hz, 1H), 7.45 (s, 5H),7.24 (dd, J=8.6, 1.7 Hz, 1H), 5.13 (s, 2H), 4.03 (s, 3H), 3.99 (d, J=1.0Hz, 3H), 1.88 (s, 3H); ESIMS m/z 459 ([M+H]⁺).

The methyl4-acetamido-3-(benzyloxy)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-picolinateproduced in the first step was dissolved in ethyl alcohol (EtOH; 100mL), and a catalytic amount of palladium hydroxide (Pd(OH)₂) in carbonwas added (2 spatula tips). The reaction mixture was stirred under ahydrogen atmosphere for 24 h, and the palladium was removed byfiltration. The filtrate was concentrated, and the residue was purifiedby flash chromatography (SiO₂; 0-50% EtOAc/hexane gradient) to providethe title compound as a white solid (0.431 g, 29% yield for the twosteps): mp 168-172° C.; ¹H NMR (400 MHz, CDCl₃) δ 11.28 (s, 1H), 8.93(d, J=1.6 Hz, 1H), 7.98 (s, 1H), 7.49 (dd, J=8.5, 7.6 Hz, 1H), 7.23 (dd,J=8.6, 1.8 Hz, 1H), 4.07 (s, 3H), 3.99 (d, J=1.1 Hz, 3H), 2.30 (s, 3H);ESIMS m/z 369 ([M+H]⁺).

Methyl 4-acetamido-6-(4-chloro-2-fluorophenyl)-3-hydroxypicolinate

Using the procedure for Example 11, the title compound was isolated asan off-white solid: mp 201-206° C.; ¹H NMR (400 MHz, CDCl₃) δ 11.27 (s,1H), 8.95 (d, J=1.5 Hz, 1H), 7.98 (s, 1H), 7.82 (t, J=8.4 Hz, 1H), 7.23(ddd, J=8.4, 2.0, 0.5 Hz, 1H), 7.18 (dd, J=10.6, 2.0 Hz, 1H), 4.07 (s,3H), 2.29 (s, 3H); ESIMS m/z 339 ([M+H]⁺).

Example 12 Preparation of methyl4-acetamido-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-methoxypicolinate(Compound 3)

Methyl4-acetamido-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-hydroxypicolinate(568 mg, 1.54 mmol), triphenylphosphine (404 mg, 1.54 mmol), diethylazodicarboxylate (243 μL, 1.54 mmol), and CH₃OH (94 μL, 2.31 mmol) werecombined in THF and allowed to stir for 24 h. Flash chromatography(SiO₂; 0-50% EtOAc/cyclohexane gradient) afforded the title compound asa yellow oil (255 mg, 43%): ¹H NMR (400 MHz, CDCl₃) δ 8.93 (d, J=1.6 Hz,1H), 8.06 (s, 1H), 7.56 (dd, J=8.5, 7.7 Hz, 1H), 7.23 (dd, J=8.6, 1.7Hz, 1H), 4.01 (s, 3H), 3.99 (d, J=1.0 Hz, 3H), 3.98 (s, 3H), 2.29 (s,3H); ESIMS m/z 383 ([M+H]⁺).

Methyl 4-acetamido-6-(4-chloro-2-fluorophenyl)-3-methoxypicolinate(Compound 4)

Using the procedure for Example 12, the title compound was isolated as ayellow oil: ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J=1.5 Hz, 1H), 7.99 (s,1H), 7.89 (t, J=8.4 Hz, 1H), 7.23 (ddd, J=8.4, 2.1, 0.6 Hz, 1H), 7.19(dd, J=10.7, 2.0 Hz, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 2.29 (s, 3H);ESIMS m/z 353 ([M+H]⁺).

Example 13 Preparation of methyl4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-methoxypicolinate(Compound 5)

Methyl4-acetamido-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-methoxypicolinate(209 mg, 0.55 mmol) was dissolved in CH₃OH (10 mL), and acetyl chloride(194 μL, 2.73 mmol) was added dropwise to the mixture. The reactionmixture was allowed to stir at 25° C. for 3 h. Additional acetylchloride (194 μL, 2.73 mmol) was then added, and the reaction mixturewas allowed to stir at 25° C. overnight. The reaction mixture wasconcentrated to dryness and purified by flash chromatography (SiO₂;0-50% EtOAc/hexane gradient) to provide the title compound as anoff-white solid (30 mg, 16%): mp 114-118° C.; ¹H NMR (400 MHz, CDCl₃) δ7.61 (dd, J=8.5, 7.8 Hz, 1H), 7.22 (dd, J=8.6, 1.8 Hz, 1H), 7.18 (d,J=2.1 Hz, 1H), 4.54 (s, 1H), 3.98 (s, 2H), 3.96 (d, J=0.8 Hz, 2H), 3.92(s, 2H); ESIMS m/z 341 ([M+H]⁺), 339 ([M−H]⁻).

Methyl 4-amino-6-(4-chloro-2-fluorophenyl)-3-methoxypicolinate (Compound6)

Using the procedure for Example 13, the title compound was isolated as awhite solid: mp 139-144° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.96 (t, J=8.5Hz, 1H), 7.25 (d, J=1.3 Hz, 1H), 7.22 (dd, J=2.0, 0.6 Hz, 1H), 7.15 (dd,J=11.1, 2.0 Hz, 1H), 6.07 (s, 2H), 3.99 (s, 3H), 3.97 (s, 3H); ESIMS m/z311 ([M+H]⁺).

Example 14 Preparation of methyl4-amino-6-(4-chlorophenyl)-3-methoxypicolinate (Compound 7)

To a solution of methyl 4-amino-6-bromo-3-methoxypicolinate (prepared asin Fields, S. C. et al. U.S. Pat. No. 6,297,197 B1, Oct. 2, 2001; 500mg, 1.9 mmol) in a 1:1 mixture of DME (4.5 mL) and H₂O (4.5 mL) wasadded 2-(4-chlorophenyl)-1,3,2-dioxaborinane (561 mg, 2.7 mmol), CsF(288 mg, 1.9 mmol) and PdCl₂(PPh₃)₂ (26 mg, 0.1941 mmol). The reactionwas heated at 110° C. in a CES microwave for 20 min. The reactionmixture was cooled to ambient temperature and diluted with CH₂Cl₂, thenwashed with water, satd aq NaHCO₃ and satd aq NaCl. The organic layerwas dried with Na₂SO₄ and filtered. The solvent was removed in vacuo.The residue was purified by normal phase chromatography (eluting with 5%Et₂O in CH₂Cl₂ with 0.05% acetic acid (HOAc)) to afford the titlecompound as a brown oil (245 mg, 44%): ¹H NMR (300 MHz, CDCl₃) δ7.90-7.81 (m, 2H), 7.46-7.36 (m, 2H), 7.12 (s, 1H), 4.56 (s, 2H), 4.01(s, 3H), 3.92 (s, 3H), ESIMS m/z 291 ([M−H]⁻).

Example 15 Preparation of 4,6-dibromo-2-chloropyridin-3-ol

2-Chloropyridin-3-ol (2 g, 15.44 mmol) and N-bromosuccinimide (NBS; 6.05g, 34.0 mmol) were dissolved in CH₃CN (75 mL) and stirred in analuminum-foil-covered round bottom flask overnight. The reaction mixturewas then concentrated under vacuum, and the residue was applied to thetop of a silica gel column utilizing CH₂Cl₂. The product was eluted fromthe column (5-40% EtOAc/hexanes gradient) to yield the title compound asan oil (4.2 g, 95%): ¹H NMR (300 MHz, CDCl₃) δ 7.60 (s, 1H), 5.85 (s,1H); ESIMS m/z 286 ([M−H]⁻).

Example 16 Preparation of4,6-dibromo-2-chloro-3-(difluoromethoxy)pyridine

Potassium carbonate (K₂CO₃; 5.01 g, 36.3 mmol) and H₂O (4 mL) were addedto a microwave reaction vessel. 4,6-Dibromo-2-chloropyridin-3-ol (0.359g, 1.25 mmol) was dissolved in CH₃CN (4 mL) and added to the microwavereaction vessel. 2-Chloro-2,2-difluoro-1-phenylethanone (0.953 g, 5.00mmol) was then added, and the microwave reaction vessel was sealed. Thereaction mixture was heated with vigorous stirring with a large stir barin a Biotage microwave reactor at 100° C. for 4 h. (The reaction mixtureis biphasic, and the reaction will not proceed to completion withoutvigorous stirring.) The reaction mixture was then partitioned betweenEtOAc and H₂O. The organic phase was washed once more with H₂O, driedand concentrated. The product was redissolved in CH₂Cl₂ and filteredthrough short plug of silica gel utilizing CH₂Cl₂ as the elutingsolvent. The eluent was concentrated to provide the title compound as alight yellow low-melting solid (0.325 g, 0.963 mmol, 77%): ¹H NMR (300MHz, CDCl₃) δ 7.73 (s, 1H), 6.63 (t, J=73.1, 1H); EIMS m/z 337.

Example 17 Preparation of6-bromo-2-chloro-3-(difluoromethoxy)pyridin-4-amine

4,6-Dibromo-2-chloro-3-(difluoromethoxy)pyridine (780 mg, 2.312 mmol)was dissolved in DMF (5 mL), and sodium azide (180 mg, 2.77 mmol) wasadded. The reaction mixture was heated at 65° C. for 2 h and theprogress of the reaction was checked by liquid chromatography-massspectrometry (LC-MS). The reaction appeared to be mostly complete. Theproduct was partitioned between Et₂O and H₂O. The aqueous phase was thenextracted twice more with Et₂O. The organic extracts were combined,diluted with petroleum ether, washed twice with H₂O, dried, andconcentrated. The product was purified by column chromatography (SiO₂,EtOAc/hexane gradient) to yield4-azido-6-bromo-2-chloro-3-(difluoromethoxy)-pyridine (0.335 g, 48.4%):¹H NMR (300 MHz, CDCl₃) δ 7.26 (s, 1H), 6.59 (t, J=73.6, 1H).

4-Azido-6-bromo-2-chloro-3-(difluoromethoxy)pyridine (0.563 g, 1.880mmol) was then dissolved in CH₃OH (15 mL), and NaBH₄ (0.107 g, 2.82mmol) was added. The reaction mixture was stirred at ambient temperaturefor 15 min at which point thin-layer chromatographic (TLC) analysisindicated complete consumption of starting material. The reactionmixture was concentrated and partitioned between EtOAc and H₂O. Theorganic phase was dried and concentrated. The product was purified byflash chromatography (SiO₂, EtOAc/hexane gradient) to yield the titlecompound as a white solid (0.398 g, 77%): mp 138-140° C.; ¹H NMR (600MHz, DMSO-d₆) δ 6.98 (t, J=73.1 Hz, 1H), 6.84 (d, J=14.6 Hz, 2H); EIMSm/z 274.

Example 18 Preparation of2-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-(difluoro-methoxy)pyridin-4-amine

6-Bromo-2-chloro-3-(difluoromethoxy)pyridin-4-amine (368 mg, 1.346mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (395mg, 1.615 mmol), PdCl₂(PPh₃)₂ (47.2 mg, 0.067 mmol), and CsF (409 mg,2.69 mmol) were combined in DME (2 mL) and H₂O (2 mL) and heated in aBiotage microwave reactor at 110° C. for 15 min. The cooled reactionmixture was partitioned between EtOAc and H₂O. The organic phase wasdried, concentrated onto silica gel, and purified by flashchromatography (SiO₂, EtOAc/hexane gradient). This process yielded thetitle compound as a white solid (0.4 g, 84%): mp 152-154° C.; ¹H NMR(300 MHz, DMSO-d₆) δ 7.63-7.50 (m, 1H), 7.42 (dd, J=8.7, 1.6, 1H), 7.16(d, J=1.8, 1H), 7.02 (t, J=73.4, 1H), 6.70 (s, 2H), 3.93 (d, J=0.8, 3H);ESIMS m/z 354 ([M+H]⁺), 352 ([M−H]⁻).

Example 19 Preparation of ethyl4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-(difluoromethoxy)picolinate(Compound 8)

2-Chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-(difluoromethoxy)pyridin-4-amine(0.2 g, 0.566 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)((C₁₇H₁₄P)₂Fe.PdCl₂; 0.041 g, 0.057 mmol), and triethylamine (Et₃N;0.158 mL, 1.133 mmol) were combined in EtOH (5 mL) in a 45 mL bombreactor. The bomb reactor was pressurized to 400 pounds per square inch(psi) with carbon monoxide (CO) and the reaction was heated at 105° C.for 40 h. The reaction mixture was then filtered through a small plug ofsilica gel utilizing EtOAc as the eluent. The filtrate was concentrated,and the product was purified by column chromatography (SiO₂,hexane/EtOAc gradient) to yield the title compound as a white solid (79mg, 35.7%): ¹H NMR (300 MHz, CDCl₃) δ 7.66 (dd, J=8.6, 7.7 Hz, 1H),7.28-7.24 (m, 1H), 7.22 (d, J=1.7 Hz, 1H), 6.72 (t, J=75.1 Hz, 1H), 4.73(s, 2H), 4.46 (q, J=7.1 Hz, 2H), 3.97 (d, J=0.8 Hz, 3H), 1.42 (t, J=7.2Hz, 3H); ESIMS m/z 391 ([M+H]⁺), 389 ([M−H]⁻); ¹⁹F NMR (376 MHz, CDCl₃)δ −79.74, −132.19.

Compound 9 in Table 1 was synthesized as in Example 19.

Example 20 Preparation of propan-2-yl 4,5,6-trichloropicolinate

Methyl 4,5,6-trichloropicolinate (prepared as in Balko, T. W. et al.U.S. Pat. No. 6,784,137 B2, Aug. 31, 2004; 14.19 g, 59.0 mmol) wasslurried in 2-propanol (150 mL) in a 250 mL round bottom flask equippedwith a Dean-Stark trap and a reflux condenser. Sulfuric acid (98% H₂SO₄;8.07 g, 82 mmol) was added, and the reaction mixture was heated toreflux. After 20 h at reflux, the majority of the 2-propanol (100 mL)was distilled overhead. The remaining reaction mixture solidified uponcooling to room temperature. The resulting solid was stirred with EtOAc(500 mL) and satd aq NaHCO₃ (500 mL). The organic layer was separated,washed with satd aq NaCl, and then filtered through Celite. The organicextract was concentrated to 150 mL by rotary evaporation. Hexane (100mL) was added, and the solution was stored at −20° C. overnight.Crystals were collected, washed with hexane and dried in air (7.58 g, mp104.6-105.7° C.). A second crop was obtained by concentration of thefiltrate to give a total of 10.36 g (65%): ¹H NMR (400 MHz, DMSO-d₆) δ8.23 (s, 1H, Pyridine H), 5.16 (septet, J=6.3 Hz, 1H, CHMe₂), 1.34 (d,J=6.3 Hz, 6H, CHMe₂); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 161.9 (CO₂R),150.6, 145.9, 145.0, 133.1, 125.4 (C3), 70.7 (CHMe₂), 21.7 (Me). Anal.Calcd for C₉H₈Cl₃NO₂: C, 40.26; H, 3.00; N, 5.22. Found: C, 40.25; H,3.02; N, 5.22.

Example 21 Preparation of propan-2-yl 4,5,6-trifluoropicolinate

A 250 mL three-neck flask was equipped with a mechanical stirrer, aDean-Stark trap with nitrogen inlet, and a thermocouple. The flask waspurged with nitrogen and CsF (23.38 g, 154 mmol) was added. AnhydrousDMSO (124 mL) was added and the suspension was evacuated/backfilled (5×)with nitrogen. The suspension was heated at 80° C. for 30 min. DMSO (20mL) was distilled off under vacuum at 75° C. to remove any residualwater. Propan-2-yl 4,5,6-trichloropicolinate (13.45 g, 50.1 mmol) wasadded against a nitrogen purge. The reaction mixture wasevacuated/backfilled (3×) and heated at 100° C. for 1 h with vigorousstirring.

A second 250 mL three-neck flask was equipped with a mechanical stirrer,a Dean-Stark trap with nitrogen inlet, and a thermocouple. The flask waspurged with nitrogen and CsF (24.41 g, 0.160 mmol) was added. AnhydrousDMSO (30 mL) was added, and the suspension was evacuated/backfilled (5×)with nitrogen. The suspension was heated to 80° C. for 30 min DMSO (22mL) was distilled off under vacuum at 75° C. to remove residual water.The cooled reaction mixture in the first flask was cannula filtered intothe second flask under nitrogen. The reaction mixture wasevacuated/backfilled (5×) and then heated at 100° C. for 1 h and thenfor an additional 90 min at 110° C. Analysis of an aliquot by gaschromatography (GC) showed 96% propan-2-yl 4,5,6-trifluoropicolinatewith only 1.4% propan-2-yl 5-chloro-4,6-difluoropicolinate present. Thecrude product solution was used directly in the amination step withoutfurther purification. Alternatively, the product can be isolated byaqueous workup, extraction with EtOAc, and drying to give a light tanoil: ¹H NMR (400 MHz, CDCl₃) δ 7.94 (dd, J_(F-H)=4.5, 8.7 Hz, 1H, H3),5.30 (septet, J_(H-H)=6.3 Hz, 1H, CHMe₂), 1.44 (d, J_(H-H)=6.3 Hz, 6H,CHMe₂); ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 161.2 (s, CO₂iPr), 157.3 (ddd,J_(F-C)=266, 8, 6 Hz, C4/C6), 152.2 (ddd, J_(F-C)=241, 12, 5 Hz, C4/C6),141.1 (dt, J_(F-C)=14, 7 Hz, C2), 137.0 (ddd, J_(F-C)=270, 31, 13 Hz,C5), 113.8 (dd, J_(F-C)=17, 4 Hz, C3), 70.4 (s, CHMe₂), 21.33 (s, Me);¹⁹F NMR (376 MHz, CDCl₃) δ −74.29 (dd, J_(F-F)=24, 22 Hz, F6), −112.67(ddd, J_(F-F)=22, 19, J_(F-H)=8.3 Hz, F4), −151.58 (ddd, J_(F-F)=24, 19,J_(F-H)=4.7 Hz, F5).

Example 22 Preparation of propan-2-yl 4-amino-5,6-trifluoropicolinate

The reaction mixture from Example 21 was filtered to remove Cs salts,and the salts were washed with DMSO (50 mL). The DMSO washing solutionwas added to the DMSO solution (150 mL) which had been saturated withammonia (NH₃) for 15 min. The flask was kept in a cold bath which keptthe temperature near 16° C. NH₃ was bubbled through the reaction mixturefor 30 min, during which time a white precipitate formed. After 90 min,analysis of an aliquot by GC showed a single major peak for the 4-aminoproduct. The reaction mixture was quenched by addition of satd aq NH₄Cl(100 mL), followed by H₂O (400 mL). The aqueous solution was extractedinto Et₂O (3×150 mL) and then EtOAc (3×150 mL). The combined organicextracts were washed with H₂O (5×150 mL) and then satd aq NaCl. Theextracts were dried (MgSO₄) and evaporated to a tan solid, which waswashed with 1:1 hexane-Et₂O to give a light tan powder (5.57 g, 51.4%overall): mp 168-170° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J_(F-H)=5.5Hz, 1H, pyridine H), 5.22 (septet, J=6.2 Hz, 1H, CHMe₂), 4.75 (s, 2H,NH₂), 1.35 (d, J=6.2 Hz, 6H, CHMe₂); ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ162.8 (CO₂R), 151.2 (dd, J_(F-C)=228, 12 Hz, C6), 146.5 (dd, J_(F-C)=9,6 Hz, C2/C4), 139.3 (dd, J_(F-C)=16, 5 Hz, C2/C4), 133.8 (dd,J_(F-C)=252, 31 Hz, C5), 112.3 (C3), 68.8 (CHMe₂), 21.5 (Me); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −91.9 (d, J_(F-F)=26.6 Hz, F6), −163.9 (dd,J_(F-F)=26.6, J_(H-F)=5.6 Hz, F5). Anal. Calcd for C₉H₁₀F₂N₂O₂: C,50.00; H, 4.66; N, 12.96. Found: C, 49.96; H, 4.65; N, 12.91.

Example 23 Preparation of propan-2-yl4-amino-6-chloro-5-fluoropicolinate

Propan-2-yl 4-amino-5,6-difluoropicolinate (4.25 g, 19.7 mmol) wasdissolved in HCl (4 M in dioxane; 65 mL) in a 100 mL Hastalloy stirredParr reactor. The reactor was heated at 100° C. for 2 h. Upon standingat room temperature overnight, a yellow crystalline solid formed. Thissolid was not soluble in EtOAc but did dissolve upon shaking with satdaq NaHCO₃ (500 mL) and EtOAc (300 mL). The aqueous layer was extractedwith EtOAc (2×250 mL). The combined organic extracts were washed withH₂O (5×50 mL) and then with satd aq NaCl. The extracts were dried(MgSO₄) and concentrated under vacuum to provide an off-white solid. Thecrude product was purified by column chromatography (120 g silicacolumn; 0-100% hexane-EtOAc gradient) to give a white solid (2.11 g,46%): mp 190.7-192.4° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 7.543 (d,J_(F-H)=5.7 Hz, 1H), 6.91 (br s, 2H, NH₂), 5.09 (septet, J=6 Hz, 1H,CHMe₂), 1.29 (d, J=6 Hz, 6H, CHMe₂); ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ162.8 (CO₂R), 144.8 (d, J_(F-C)=12 Hz, C2/C4), 143.4 (d, J_(F-C)=254 Hz,C5), 142.7 (d, J_(F-C)=4.8 Hz, C2/C4), 136.5 (d, J_(F-C)=17 Hz, C6),112.8 (d, J_(F-C)=5 Hz, C3), 68.9 (CHMe₂), 21.6 (Me); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −141.0 (d, J_(F-H)=6 Hz). Anal. Calcd for C₉H₁₀ClFN₂O₂: C,46.47; H, 4.33; N, 13.75. Found: C, 46.50; H, 4.33; N, 11.96.

Example 24 Preparation of methyl 4-amino-6-chloro-5-fluoropicolinate

Isopropyl 4-amino-6-chloro-5-fluoropicolinate (1.35 g, 5.80 mmol) wasdissolved in anhydrous CH₃OH (50 mL), treated with titanium(IV)isopropoxide (300 mg, 2.2 mmol), and heated at reflux for 4 h. Aftercooling, the volatiles were removed under vacuum, and the residue wastaken up in EtOAc (30 mL). This solution was stirred with H₂O (1 mL) for20 min and then filtered through diatomaceous earth. The filtrate waswashed with satd aq NaCl (10 mL), dried (Na₂SO₄), and evaporated to givethe title compound (1.2 g, 97%): mp 180-183° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 7.45 (d, J=6.0 Hz, 1H), 6.93 (s, 2H), 3.83 (s, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −131.36, −131.42, −135.47, −135.53; EIMS m/z 204.

Another method of producing this intermediate is as follows:

To a solution of 4-amino-6-chloro-5-fluoropicolinic acid (23.8 g, 125mmol) in MeOH (400 ml), cooled in an ice water bath, thionyl chloride(11.78 ml, 162 mmol) was added. The reaction mixture was heated to aninternal temperature of 50° C., for 8 hours. The reaction mixture wasthen diluted with H₂O, and extracted with EtOAC (3×100 mL). The combinedorganics were washed with Sat. NaCl, dried over Mg Sulfate, filtered andconcentrated under vacuum to give methyl4-amino-6-chloro-5-fluoropicolinate (21.9 g, 107 mmol, 86% yield).

Example 25 Preparation of methyl4-amino-6-chloro-5-fluoro-3-iodopicolinate

Methyl 4-amino-6-chloro-5-fluoropicolinate (2.2 g, 10.8 mmol) wasdissolved in methyl alcohol (20 mL). The solution was treated withperiodic acid (880 mg, 3.9 mmol) and iodine (2.2 g, 8.6 mmol) and thenheated at reflux for 20 h. The mixture was cooled, and the volatileswere removed under vacuum. The residue was dissolved in EtOAc (50 mL)and then stirred with 10% NaHSO₃ solution (20 mL) for 10 min. Theorganic phase was separated and washed with satd aq NaCl (10 mL), dried(Na₂SO₄) and evaporated. The residue was purified by silica gelchromatography (5-50% EtOAc-hexane gradient) to give the title compoundas a light orange solid (2.5 g, 70%): mp 149-151° C.; ESIMS m/z 330([M]⁺); ¹H NMR (400 MHz, CDCl₃) δ 5.17 (s, 2H, NH₂), 3.97 (s, 3H, OMe);¹⁹F NMR (376 MHz, CDCl₃) δ −135.79 (s).

Example 26 Preparation of methyl4-amino-6-chloro-5-fluoro-3-methoxypicolinate (Compound 10)

To a dry 1 liter (L) flask was added methyl4-amino-6-chloro-5-fluoro-3-iodopicolinate (50 g, 151 mmol) and cesiumcarbonate (Cs₂CO₃; 99 g, 303 mmol). CH₃OH (378 mL) was added, and thesolution was sparged with nitrogen for 10 min 1,10-Phenanthroline (6.00g, 30.3 mmol) and copper(I) iodide (CuI; 2.88 g, 15.13 mmol) were added,and the flask was fitted with a reflux condenser and heated to 65° C.under nitrogen. After 12 h, CuI (2.88 g, 15.13 mmol) was again added tothe reaction mixture, and heating was continued until consumption of theiodopicolinate was observed. The reaction mixture was cooled to roomtemperature, filtered through Celite, and concentrated in vacuo. To thecrude residue was added EtOAc (100 mL) and H₂O (100 mL). The layers wereseparated, and the aqueous phase was acidified to pH=2 with concentrated(conc) HCl and subsequently extracted with EtOAc (3×100 mL). The organicextracts were combined, washed with satd aq NaCl, dried (Na₂SO₄),filtered, and concentrated in vacuo to afford4-amino-6-chloro-5-fluoro-3-methoxypicolinic acid.

The crude acid was treated with CH₃OH (200 mL) saturated with hydrogenchloride (HCl; g), and the reaction mixture was heated at 50° C. for 4h. Upon consumption of the acid, the mixture was cooled to roomtemperature and concentrated in vacuo. The residue was dissolved in Et₂O(100 mL) and washed with H₂O (50 mL) and satd aq NaCl (50 mL). Theorganic extracts were combined, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude ester was purified using a TeledyneISCO purification system with a gradient eluent system of EtOAc andhexanes, followed by recrystallization from water to provide the titlecompound as a purple solid (10.1 g, 36% overall yield for the twosteps): ¹H NMR (400 MHz, CDCl₃) δ 4.67 (s, 2H), 3.96 (s, 3H), 3.93 (s,3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −135.15 (s); EIMS m/z 234.

Example 27 Preparation of methyl4-amino-5-fluoro-6-(3-fluoro-4-(trifluoromethyl)-phenyl)picolinate

To a 5 mL microwave vial was added methyl4-amino-6-chloro-5-fluoropicolinate (500 mg, 2.44 mmol),2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(851 mg, 2.93 mmol), potassium fluoride (KF; 369 mg, 6.35 mmol), andPdCl₂(PPh₃)₂ (172 mg, 0.24 mmol). Subsequently, CH₃CN (3.0 mL) and H₂O(3.0 mL) were added, and the reaction vial was sealed and heated in aBiotage microwave at 115° C. for 20 min. The reaction mixture was cooledto room temperature and diluted with EtOAc (5 mL). The layers wereseparated and the aqueous phase was extracted with EtOAc (2×2 mL). Theorganic extracts were combined, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude product was purified using a TeledyneISCO purification system with a gradient eluent system of EtOAc andhexanes to yield the title compound as a yellow solid (570 mg, 70%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.94 (dt, J=12.3, 6.2 Hz, 3H), 7.52 (d, J=6.4Hz, 1H), 6.80 (s, 2H), 3.86 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−59.96, −59.99, −115.69, −144.18, −144.20; ESIMS m/z 333.21 ([M+H]⁺).

Methyl 4-amino-6-(4-chlorophenyl)-5-fluoropicolinate

Using the procedure for Example 27, the title compound was isolated asan off-white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (d, J=7.4 Hz, 2H),7.58 (d, J=8.6 Hz, 2H), 7.47 (d, J=6.3 Hz, 1H), 6.67 (s, 2H), 3.84 (s,3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −145.01; ESIMS m/z 281.48 ([M+H]⁺),279.85 ([M−H]⁻).

Example 28 Preparation of methyl4-amino-5-fluoro-6-(3-fluoro-4-(trifluoromethyl)phenyl)-3-iodopicolinate

Methyl 4-amino-5-fluoro-6-(3-fluoro-4-(trifluoromethyl)phenyl)picolinate(500 mg, 1.51 mmol) was dissolved in CH₃OH (0.6 mL) in a round bottomflask. Periodic acid (123 mg, 0.542 mmol) and iodine (306 mg, 1.204mmol) were added, and the reaction mixture was heated at reflux with adrying tube for 12 h. The reaction mixture was cooled to roomtemperature and concentrated in vacuo. The crude product was dissolvedin Et₂O and washed with 10% sodium thiosulfate (Na₂S₂O₃; 2×5 mL). Theorganic extracts were combined, dried over anhydrous Na₂SO₄, filtered,and concentrated providing methyl4-amino-5-fluoro-6-(3-fluoro-4-(trifluoromethyl)phenyl)-3-iodopicolinate(635 mg, 92%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (dd, J=14.8, 6.8 Hz,1H), 7.90-7.82 (m, 2H), 6.89 (s, 2H), 3.88 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −60.02 (t, J=12.4 Hz), −115.50 (td, J=12.2, 7.6 Hz), −139.91(s); ESIMS m/z 459.62 ([M+H]⁺).

Methyl 4-amino-6-(4-chlorophenyl)-5-fluoro-3-iodopicolinate

Using the procedure for Example 28, the title compound was isolated as ared semi-solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (dd, J=8.5, 1.1 Hz,2H), 7.57 (d, J=8.7 Hz, 2H), 6.75 (s, 2H), 3.87 (s, 3H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −140.67; ESIMS m/z 407.69 ([M+H]⁺).

Methyl 4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-iodopicolinate(Compound 91)

Using the procedure for Example 28, the title compound was isolated as apale pink solid: ¹H NMR (400 MHz, CDCl3) δ 7.77-7.84 (m, 1H), 7.68-7.77(m, 2H), 6.80 (s, 2H), 3.88 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−140.15, −115.85. ESIMS m/z 425 ([M+H]⁺), 423 ([M−H]⁻).

Example 29 Preparation of4-amino-5-fluoro-6-(3-fluoro-4-(trifluoromethyl)phenyl)-3-methoxypicolinicacid (Compound 11)

Methyl 4-amino-5-fluoro-3-iodopicolinate (0.2 g, 0.437 mmol), Cs₂CO₃(0.284 g, 0.873 mmol), 1,10-phenanthroline (17 mg, 0.087 mmol) and CuI(8.3 mg, 0.044 mmol) were added to a dry round bottom flask undernitrogen. CH₃OH (4.4 mL) was added, and the reaction was heated at 70°C. until complete consumption of the iodopicolinate. The reactionmixture was cooled to room temperature, filtered through Celite, andconcentrated in vacuo. The crude residue was acidified with 2 M HCl andextracted with EtOAc (3×5 mL). The organic extracts were combined, dried(Na₂SO₄), filtered, and concentrated in vacuo to provide the titlecompound (0.126 g, 80%) as a red semi-solid: ¹H NMR (400 MHz, CDCl₃) δ7.83-7.63 (m, 4H), 4.89 (s, 2H), 4.08 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −59.91, −59.93, −59.94, −115.72, −115.75, −140.39; ESIMS m/z347.81 ([M−H]⁻).

Example 30 Preparation of methyl4-amino-5-fluoro-3-methoxy-6-vinylpicolinate (Compound 12)

A mixture of methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (405mg, 1.73 mmol), tributyl(vinyl)stannane (1.097 g, 3.46 mmol), andPdCl₂(PPh₃)₂ (181 mg, 0.26 mmol) in 1,2-dichloroethane (3.5 mL) washeated at 120° C. in a Biotage microwave for 30 min Columnchromatography (0-40% EtOAc/hexanes) of the crude reaction mixtureprovided the title compound as a yellow oil (0.38 g, 97%): ¹H NMR (400MHz, CDCl₃) δ 6.88 (ddd, J=17.5, 11.1, 1.4 Hz, 1H), 6.33 (dd, J=17.5,1.6 Hz, 1H), 5.57 (ddd, J=11.1, 1.6, 0.7 Hz, 1H), 4.47 (s, 2H), 3.97 (s,3H), 3.91 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −143.2; ESIMS m/z 227([M+H]⁺).

Example 31 Preparation of methyl4-amino-6-ethyl-5-fluoro-3-methoxypicolinate (Compound 13)

To methyl 4-amino-5-fluoro-3-methoxy-6-vinylpicolinate (0.32 g, 1.42mmol) in EtOAc (5 mL) was added 10% palladium on carbon (Pd/C; 0.16 g,0.15 mmol). The mixture was stirred under an atmosphere of hydrogenovernight, filtered through Celite and concentrated to provide methyl4-amino-6-ethyl-5-fluoro-3-methoxypicolinate (0.21 g, 0.92 mmol) as awhite solid: mp 110.5-113.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 4.41 (s, 2H),3.96 (s, 3H), 3.90 (s, 3H), 2.81 (qd, J=7.6, 2.7 Hz, 2H), 1.26 (t, J=7.6Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 165.2, 148.6, 146.2, 144.2, 136.8,136.1, 61.5, 52.7, 25.3, 12.9; ¹⁹F NMR (376 MHz, CDCl₃) δ −142.6; EIMSm/z 228.

Example 32 Preparation of methyl4-amino-5-fluoro-6-(3-fluoro-4-(trimethylsilyl)phenyl)-3-methoxypicolinate(Compound 14)

To a 5-mL microwave safe vial were added methyl4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.400 g, 1.705 mmol),(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane(0.690 g, 2.344 mmol), KF (0.297 g, 5.11 mmol), and PdCl₂(PPh₃)₂ (0.120g, 0.170 mmol). A mixture of H₂O (1 mL) and CH₃CN (2 mL) was added, andthe reaction vial was capped and placed in a Biotage Initiator microwavereactor for 20 min at 115° C. with external infrared (IR)-sensortemperature monitoring from the side of the vessel. Upon cooling to roomtemperature, the reaction mixture was diluted with CH₂Cl₂ (25 mL) andH₂O (25 mL), and the organic layer was filtered through a cotton plug.An additional extraction using EtOAc (25 mL) was combined with theCH₂Cl₂ and dried over Na₂SO₄ (50 g). Following filtration of thecombined organics through a cotton plug and concentration on a rotaryevaporator, the residue was purified using a Teledyne ISCO purificationsystem with a gradient eluent system of CH₂Cl₂ and EtOAc to yield thetitle compound as a light pink oil (333 mg, 53%): ¹H NMR (400 MHz,CDCl₃) δ 7.66 (d, J=7.6 Hz, 1H), 7.55 (d, J=9.8 Hz, 1H), 7.46 (dd,J=7.6, 5.9 Hz, 1H), 4.57 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 0.33 (s,9H); ¹⁹F NMR (376 MHz, CDCl₃) δ −100.72, −140.12; ESIMS m/z 367([M+H]⁺).

Example 33 Preparation of methyl4-amino-6-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-fluoro-3-methoxypicolinate(Compound 15)

To a 20 mL microwave vial were added methyl4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.80 g, 3.41 mmol),(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)trimethylsilane(1.28 g, 4.09 mmol), sodium carbonate (Na₂CO₃; 0.36 g, 3.41 mmol), andPdCl₂(PPh₃)₂ (0.24 g, 0.34 mmol). Subsequently, CH₃CN (5.7 mL) and H₂O(5.7 mL) were added, and the reaction vial was sealed and heated in aBiotage microwave to 115° C. for 20 min. The reaction mixture was cooledto room temperature and diluted with EtOAc (10 mL). The organic layerwas separated and the aqueous phase was extracted with EtOAc (2×2 mL).The organic extracts were combined, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified using a TeledyneISCO purification system with a gradient eluent system of EtOAc andhexanes to yield methyl4-amino-6-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-fluoro-3-methoxypicolinate(0.99 g, 75%) as a white solid: mp 123-125° C.; ¹H NMR (400 MHz, CDCl₃)δ 7.32 (ddd, J=7.6, 5.5, 1.1 Hz, 1H), 7.20 (ddd, J=7.7, 4.5, 1.4 Hz,1H), 4.60 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 0.41-0.28 (m, 9H); ¹⁹FNMR (376 MHz, CDCl₃) δ −127.39, −127.45, −127.46, −137.48, −137.56,−140.78, −140.85, −140.86, −140.92; ESIMS m/z 383.20 ([M−H]⁻).

Methyl 4-amino-5-fluoro-3-methoxy-6-(4-(trimethylsilyl)phenyl)picolinate(Compound 16)

Using the procedure for Example 33, the title compound was isolated as ared solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.80-7.70 (m, 2H), 7.63 (d, J=8.2Hz, 2H), 6.49 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −141.15; ESIMS m/z 349.59 ([M+H]⁺).

Example 34 Preparation of methyl4-amino-6-(2,5-difluoro-4-(trimethylsilyl)phenyl)-5-fluoro-3-methoxypicolinate(Compound 17)

(2,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane(1.785 g, 4.69 mmol, 82% purity), methyl4-amino-6-chloro-5-fluoro-3-methoxypicolinate (1 g, 4.26 mmol), Na₂CO₃(0.542 g, 5.11 mmol), and PdCl₂(PPh₃)₂ (0.299 g, 0.426 mmol) weresuspended in a 3:1 mixture of CH₃CN (7.99 mL) and H₂O (2.66 mL) in amicrowave vial. The reaction mixture was irradiated at 90° C. for 20min. The reaction was monitored by TLC and ultra performance liquidchromatography (UPLC). The mixture was poured into a half satd aq NaClsolution and extracted with EtOAc (3×). The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography (SiO₂, ISCO, 120 g column, hexanes/EtOAcgradient) to afford the title compound as a yellow solid (0.977 g, 60%):mp 137-139° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.23 (dd, J=7.9, 5.1 Hz, 1H),7.12 (dd, J=9.3, 4.0 Hz, 1H), 4.60 (s, 2H), 3.97 (s, 3H), 3.97 (s, 3H),0.33 (d, J=0.8 Hz, 9H); ¹⁹F NMR (376 MHz, CDCl₃) δ −107.12, −121.88,−137.27; ESIMS m/z 384 ([M]⁺).

Methyl4-amino-5-fluoro-6-(2-fluoro-4-(trimethylsilyl)phenyl)-3-methoxypicolinate(Compound 18)

Using the procedure for Example 34, the title compound was isolated as ayellow solid: mp 127-129° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.56 (t, J=7.2Hz, 1H), 7.37 (dd, J=7.5, 0.7 Hz, 1H), 7.26 (dd, J=10.1, 0.8 Hz, 1H),4.57 (s, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 0.28 (s, 9H); ¹⁹F NMR (376MHz, CDCl₃) δ −116.17, −137.36; ESIMS m/z 367 ([M+H]⁺).

Example 35 Preparation of methyl4-amino-6-(4-bromo-2,3-difluorophenyl)-5-fluoro-3-methoxypicolinate(Compound 19)

Methyl 4-amino-5-fluoro-3-methoxy-6-(4-(trimethylsilyl)phenyl)picolinate(300 mg, 0.78 mmol) was dissolved in CH₃CN (3.9 mL) and then bromine(0.402 mL, 7.8 mmol) was added. The reaction mixture was stirred at roomtemperature for 12 h. The mixture was partitioned between CH₂Cl₂ (2 mL)and H₂O (1 mL), and 10% Na₂S₂O₃ (2 mL) was added. The layers wereseparated, and the aqueous phase was further extracted with CH₂Cl₂ (3×2mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated in vacuo. The product was purified using a Teledyne ISCOpurification system with a gradient eluent system of EtOAc and hexanesto yield the title compound as a white solid (123 mg, 40%): ¹H NMR (400MHz, DMSO-d₆) δ 7.67 (ddd, J=8.3, 6.3, 1.7 Hz, 1H), 7.40-7.27 (m, 1H),6.68 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−131.44, −131.45, −131.46, −131.50, −131.50, −131.51, −131.52, −136.12,−136.14, −136.19, −136.20, −136.22, −136.26, −136.28, −138.65, −138.72;ESIMS m/z 392.06 ([M+H]⁺).

Compounds 20-22 in Table 1 were synthesized as in Example 35.

Example 36 Preparation of methyl4-amino-5-fluoro-6-(4-iodophenyl)-3-methoxypicolinate (Compound 23)

Methyl 4-amino-5-fluoro-3-methoxy-6-(4-(trimethylsilyl)phenyl)picolinate(239 mg, 0.686 mmol) was dissolved in 1,2-dichloroethane (3.4 mL) andiodine monochloride (78 μL, 1.557 mmol). The reaction mixture wasstirred at room temperature for 48 h. The mixture was quenched with 10%Na₂S₂O₃ (2 mL) and stirred at room temperature for 1 h. The mixture wasextracted with CH₂Cl₂ (3×5 mL), and the combined organic extracts weredried over Na₂SO₄ and concentrated in vacuo. The product was purifiedvia RP-HPLC (CH₃CN/H₂O) to yield the title compound as an orange solid(270 mg, 98%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.86 (d, J=8.5 Hz, 2H),7.65-7.53 (m, 2H), 6.54 (s, 2H), 3.86 (s, 3H), 3.77 (s, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −140.64; ESIMS m/z 403.61 ([M+H]⁺).

Compounds 24-28 in Table 1 and methyl4-amino-6-(4-chloro-2,3-difluorophenyl)-5-fluoro-3-methoxypicolinatewere synthesized as in Example 36.

Example 37 Preparation of methyl4-amino-5-fluoro-6-(4-formylphenyl)-3-methoxypicolinate (Compound 29)

To a 5-mL microwave safe vial was added methyl4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.400 g, 1.705 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.435 g,1.875 mmol), KF (0.297 g, 5.11 mmol), and PdCl₂(PPh₃)₂ (0.120 g, 0.170mmol). A mixture of H₂O (1 mL) and CH₃CN (2 mL) was added, and thereaction vial was capped and placed in a Biotage Initiator microwavereactor for 20 min at 115° C. with external IR-sensor temperaturemonitoring from the side of the vessel. Upon cooling to roomtemperature, the reaction mixture was diluted with CH₂Cl₂ (25 mL) andH₂O (25 mL), and the organic layer was filtered through a cotton plug.An additional extraction using EtOAc (25 mL) was combined with theCH₂Cl₂ and dried over Na₂SO₄ (50 g). Following filtration of thecombined organics through a cotton plug and concentration on a rotaryevaporator, the residue was purified using a Teledyne ISCO purificationsystem with a gradient eluent system of CH₂Cl₂ and EtOAc to yield thetitle compound as a tan solid (335 mg, 65%): ¹H NMR (400 MHz, CDCl₃) δ10.08 (s, 1H), 8.09 (dd, J=8.3, 1.5 Hz, 2H), 8.03-7.93 (m, 2H), 4.62 (s,2H), 4.00 (s, 3H), 3.98 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −139.69;ESIMS m/z 305 ([M+H]⁺), 303 ([M−H]⁻).

Example 38 Preparation of methyl4-amino-6-(4-ethynylphenyl)-5-fluoro-3-methoxypicolinate (Compound 30)

To a 20 mL reaction vial were added methyl4-amino-5-fluoro-6-(4-formylphenyl)-3-methoxypicolinate (0.41 g, 1.347mmol), K₂CO₃ (0.372 g, 2.69 mmol), and CH₃OH (20 mL). Dimethyl1-diazo-2-oxopropylphosphonate (0.311 g, 1.617 mmol) was added in oneportion. After stirring for 4 h, the reaction mixture was diluted withEt₂O (50 mL) and washed with 5% NaHCO₃ (25 mL). The organic layer wasdried over MgSO₄ (5 g), filtered, and concentrated on a rotaryevaporator. The resulting residue was purified using a Teledyne ISCOpurification system with a gradient eluent system of CH₂Cl₂ and EtOAc toyield the title compound as an off-white solid (297 mg, 73%): ¹H NMR(400 MHz, CDCl₃) δ 7.93-7.85 (m, 2H), 7.62-7.53 (m, 2H), 4.57 (s, 2H),3.98 (s, 3H), 3.96 (s, 3H), 3.15 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ−139.97; ESIMS m/z 301 ([M+H]⁺), 299 ([M−H]⁻).

Example 39 Preparation of methyl4-amino-6-(4-chlorophenyl)-5-fluoro-3-methoxypicolinate (Compound 31)

To a solution of methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate(200 mg, 0.852 mmol) in CH₃CN (1.246 mL) and H₂O (1.246 mL) were added2-(4-chlorophenyl)-1,3,2-dioxaborinane (251 mg, 1.279 mmol), KF (149 mg,2.56 mmol), palladium(II) acetate (Pd(OAc)₂; 19.14 mg, 0.085 mmol), andtriphenylphosphine-3,3′,3″-trisulfonic acid trisodium salt (100 mg,0.170 mmol). The reaction mixture was then heated in a bench top Biotagemicrowave at 150° C. for 5 min. The reaction mixture was diluted withCH₂Cl₂ and washed with H₂O. The organic layer was separated, dried overMgSO₄, filtered and concentrated. The crude residue was purified bynormal phase chromatography (eluting with 10% EtOAc/40% CH₂Cl₂/50%hexanes) to afford the title compound as a tan solid (191 mg, 72.1%): mp93-94° C.; ¹H NMR (400 MHz, acetone-d₆) δ 7.96 (dd, J=8.8, 1.4 Hz, 2H),7.57-7.49 (m, 2H), 5.93 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), ESIMS m/z311 ([M+H]⁺), 309 ([M−H]⁻).

Compound 32 in Table 1 was synthesized as in Example 39.

Example 40 Preparation of methyl4-amino-6-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-5-fluoro-3-methoxypicolinate(Compound 33)

Methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.400 g, 1.705mmol),2-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(prepared as described in WO2009029735 A1 20090305; 0.671 g, 2.216mmol), PdCl₂(PPh₃)₂ (0.120 g, 0.170 mmol), and KF (0.258 g, 4.43 mmol)were combined in a 1:1 mixture of CH₃CN (2.84 mL) and H₂O (2.84 mL). Thereaction mixture was irradiated in a Biotage microwave at 115° C. in asealed vial for 20 min. The cooled reaction mixture was partitionedbetween EtOAc and H₂O. The organic phase was dried and concentrated. Theproduct was purified by flash chromatography (SiO₂, 5-40% EtOAc inhexane gradient) to provide the title compound as a sticky brown-orangesolid (0.545 g, 81%): ¹H NMR (400 MHz, CDCl₃) δ 7.53-7.46 (m, 1H), 7.29(dt, J=8.4, 1.1 Hz, 1H), 6.39-6.03 (m, 1H), 4.61 (s, 2H), 3.97 (d, J=2.1Hz, 6H), 1.85-1.68 (m, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −113.81, −113.87,−113.90, −113.95, −137.05, −137.14, −175.47, −175.52; ESIMS m/z 375([M+H]⁺), 373 ([M−H]⁻).

Compounds 34-43 and 69 in Table 1 were synthesized as in Example 40.

Example 41 Preparation of methyl4-amino-5-chloro-6-(4-chlorophenyl)-3-methoxypicolinate (Compound 44)

To a 5 mL microwave vial were added methyl4-amino-6-bromo-5-chloro-3-methoxypicolinate (200 mg, 0.677 mmol),4-chlorophenylboronic acid (116 mg, 0.744 mmol), KF (102 mg, 1.760mmol), and PdCl₂(PPh₃)₂ (48 mg, 0.068 mmol). Subsequently, CH₃CN (1.1mL) and H₂O (1.1 mL) were added, and the reaction vial was sealed andheated in a Biotage microwave at 115° C. for 20 min. The reactionmixture was cooled to room temperature and diluted with EtOAc (3 mL).The organic phase was separated, and the aqueous phase was washed withEtOAc (2×2 mL). The organic extracts were combined, dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was using aTeledyne ISCO purification system with a gradient eluent system of EtOAcand hexanes to yield the title compound as a white solid (106 mg, 47%):mp 139-141° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 7.60-7.54 (m, 2H), 7.54-7.47(m, 2H), 6.68 (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H); ESIMS m/z 326.00([M−H]⁻).

Example 42 Preparation of4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-3-methoxypicolinicacid (Compound 45)

Methyl4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-3-methoxypicolinate(0.77 g, 2.15 mmol) was dissolved in CH₃OH (14 mL) and 2 N sodiumhydroxide (NaOH; 4.3 mL) was added. The solution was stirred at roomtemperature overnight, acidified with 2 N HCl and concentrated to removethe majority of CH₃OH. The precipitate that formed was filtered, washedwith H₂O and dried under vacuum to provide the title compound as a whitesolid (668 mg, 90%): mp 143-146° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.30 (dd,J=8.5, 1.6 Hz, 1H), 7.19 (dd, J=8.4, 6.8 Hz, 1H), 4.83 (s, 2H), 4.07 (s,3H), 4.02 (d, J=1.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −128.66,−128.74, −134.93, −135.01; ESIMS m/z 345 ([M+H]⁺), 343 ([M−H]⁻).

Compounds 46-65 and 70-71 in Table 1 were synthesized as in Example 42.

Example 43 Preparation of benzyl4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-3-methoxypicolinate(Compound 66)

To a solution of4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-3-methoxypicolinicacid (140 mg, 0.406 mmol) in DMSO (1.354 mL) were added K₂CO₃ (67.4 mg,0.487 mmol) and (bromomethyl)benzene (76 mg, 0.447 mmol). The reactionmixture was heated at 100° C. for 5 min in a Biotage microwave. Thereaction mixture was then diluted with H₂O and extracted with CH₂Cl₂.The organic extracts were separated from the aqueous layer in a Biotagephase separator. The organic layer was then concentrated, and theresidue was purified by flash chromatography (eluting with 0-50% acetonein hexanes) to afford a white solid (125 mg, 69%): mp 119° C.; ¹H NMR(400 MHz, acetone-d₆) δ 7.56-7.49 (m, 2H), 7.43-7.27 (m, 5H), 5.98 (s,2H), 5.40 (s, 2H), 3.97 (d, J=1.1 Hz, 3H), 3.85 (s, 3H), ESIMS m/z 436([M+H]⁺), 434 ([M−H]⁻).

Example 44 Preparation of ethyl4-amino-6-(4-chloro-2-fluorophenyl)-3-(2,2,2-trifluoro-ethoxy)picolinate(Compound 67)

To a mixture of 2,2,2-trifluoroethanol (3.9 mL) and K₂CO₃ (54 mg, 3.9mmol) was added (E)-ethyl3-bromo-6-(4-chloro-2-fluorophenyl)-4-(((methylsulfonyl)oxy)imino)-1,4,5,6-tetrahydropicolinate(prepared as in Renga, J. M. et al. U.S. Patent Appl. Publ. 2010/0311594A1, Dec. 9, 2010; 450 mg, 1 mmol). The mixture was stirred for 30 min,then diluted with Et₂O and washed with 1 M HCl. The organic extractswere dried with Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by flash chromatography (eluting with 0-50% EtOAc/hexanesaffording an off-white solid: (190 mg, 74%): mp 123-135° C.; ¹H NMR (300MHz, CDCl₃) δ 8.00 (t, J=8.5 Hz, 1H), 7.23 (m, 3H), 7.15 (dd, J=11.1,2.0 Hz, 1H), 4.59 (s, 2H), 4.46 (m, 4H), 1.44 (t, J=7.1 Hz, 3H); ESIMSm/z 393 ([M+H]⁺), 391 ([M−H]⁻).

Compound 68 in Table 1 was synthesized as in Example 44.

Example 45 Preparation of methyl 4-amino-3-methoxy-6-vinylpicolinate(Compound 85)

Methyl 4-amino-6-bromo-3-methoxypicolinate (1 g, 3.83 mmol),tributyl(vinyl)stannane (1.822 g, 5.75 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.403 g, 0.575 mmol) inDCE (12.77 ml) were stirred at 70° C. overnight. The mixture wasadsorbed onto celite and purified by flash column chromatography (ISCO,SiO2 40 g, hexane/EtOAc 100:0 to 0:100 gradient) to afford methyl4-amino-3-methoxy-6-vinylpicolinate (263 mg, 1.263 mmol, 33% yield) as ayellow oil. EIMS m/z 208; ¹H NMR (400 MHz, CDCl₃) δ 6.86 (s, 1H), 6.71(dd, J=17.6, 10.9 Hz, 1H), 5.98 (dd, J=17.6, 1.0 Hz, 1H), 5.42 (dd,J=10.9, 1.0 Hz, 1H), 4.45 (s, 2H), 3.97 (s, 3H), 3.87 (s, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 165.94, 152.06, 148.02, 143.34, 141.60, 136.73,118.02, 108.63, 61.49, 52.84.

Example 46 Preparation of methyl4-[bis(tert-butoxycarbonyl)amino]-6-ethenyl-3-methoxypyridine-2-carboxylate

To a solution of methyl 4-amino-3-methoxy-6-vinylpicolinate (0.263 g,1.263 mmol) in DCE (6.32 ml) was added di-tert-butyl dicarbonate (0.827g, 3.79 mmol) and N,N-dimethylpyridin-4-amine (0.023 g, 0.189 mmol). Thereaction mixture was stirred at room temperature overnight. The mixturewas adsorbed onto celite and purified by flash column chromatography(ISCO, SiO2, 24 g, hexane/EtOAc 100:0 to 0:100 gradient) to affordmethyl4-[bis(tert-butoxycarbonyl)amino]-6-ethenyl-3-methoxypyridine-2-carboxylate(382 mg, 0.935 mmol, 74.0% yield) as a colorless oil. ESIMS m/z 409([M+H]⁺); ¹H NMR (400 MHz, CDCl₃) δ 7.30 (s, 1H), 6.81 (dd, J=17.5, 10.9Hz, 1H), 6.08 (d, J=17.4 Hz, 1H), 5.51 (d, J=11.1 Hz, 1H), 3.99 (s, 3H),3.86 (s, 3H), 1.42 (s, 18H).

Example 47 Preparation of methyl4-[bis(tert-butoxycarbonyl)amino]-6-formyl-3-methoxypyridine-2-carboxylate

Ozone was bubbled through a solution of methyl4-[bis(tert-butoxycarbonyl)amino]-6-ethenyl-3-methoxypyridine-2-carboxylate(0.382 g, 0.935 mmol) in CH₂Cl₂ (9.35 ml) at −78° C. until the solutionturned blue. Oxygen was bubbled through the reaction mixture until thesolution turned yellow and triphenylphosphine (0.294 g, 1.122 mmol) wasadded. The reaction mixture was allowed to warm to room temperature andwas stirred overnight. The reaction mixture was then adsorbed ontocelite and the residue was purified by flash column chromatography(ISCO, SiO2 24 g, hexanes/EtOAc 100:0 to 0:100 gradient) to affordmethyl4-[bis(tert-butoxycarbonyl)amino]-6-formyl-3-methoxypyridine-2-carboxylate(279 mg, 0.680 mmol, 72.7% yield) as a light yellow oil. ESIMS m/z 411([M−H]+); ¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 7.88 (s, 1H), 4.05(s, 3H), 3.95 (s, 3H), 1.43 (s, 18H).

Example 48 Preparation of 4-amino-6-(difluoromethyl)-3-methoxypicolinate(Compound 92)

To a 0° C. solution of methyl4-[bis(tert-butoxycarbonyl)amino]-6-formyl-3-methoxypyridine-2-carboxylate(0.279 g, 0.680 mmol) in CH₂Cl₂ (2.72 ml) was added DEOXO-FLUOR® (0.251ml, 1.360 mmol). The mixture was stirred at 0° C. for 1 h (reactioncompleted based on TLC and LC). TFA (1 mL) was then added and thereaction mixture was allowed to slowly warm to room temperature and wasstirred overnight. The mixture was poured into saturated NaHCO₃ andextracted with EtOAc (2×). The combined organic layers were dried overMgSO4, filtered and concentrated. The residue was purified by flashcolumn chromatography (ISCO, SiO2 12 g, hexanes/EtOAc 100:0 to 0:100gradient) to afford methyl4-amino-6-(difluoromethyl)-3-methoxypicolinate (89 mg, 0.383 mmol, 56.4%yield) as a white solid. ESIMS m/z 233 ([M+H]+); ¹H NMR (400 MHz, CDCl₃)δ 7.06 (s, 1H), 6.54 (t, J=55.4 Hz, 1H), 4.69 (s, 2H), 3.98 (s, 3H),3.90 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −114.65.

Example 49 Preparation of 4-amino-6-(1-ethoxyvinyl)-3-methoxypicolinate

Methyl 4-amino-6-bromo-3-methoxypicolinate (2 g, 7.66 mmol),tributyl(1-ethoxyvinyl)stannane (4.15 g, 11.49 mmol) andbis(triphenylphosphine)palladium(ii) chloride (0.807 g, 1.149 mmol) inDCE (19.15 ml) were stirred under microwave irradiation (120° C., 30min). The reaction was not completed (LC). Additional tin reagent (1equiv) and palladium catalyst (0.15 equiv) were added and the reactionmixture was stirred under microwave irradiation (120° C., 30 min). Themixture was adsorbed onto celite and purified by flash columnchromatography (ISCO, SiO2 80 g, hexane/EtOAc 100:0 to 0:100 gradient)to afford methyl 4-amino-6-(1-ethoxyvinyl)-3-methoxypicolinate (1.68 g,6.66 mmol, 87% yield) as a yellow solid. Mp 72-73° C.; EIMS m/z 253([M+H]⁺); ¹H NMR (400 MHz, CDCl₃) δ 7.15 (s, 1H), 5.34 (d, J=2.0 Hz,1H), 4.45 (s, 2H), 4.31 (d, J=1.9 Hz, 1H), 3.96 (s, 3H), 3.92 (q, J=7Hz, 2H), 3.86 (s, 3H), 1.41 (t, J=7.0 Hz, 3H).

Example 50 Preparation of methyl 6-acetyl-4-amino-3-methoxypicolinate

To a solution of methyl 4-amino-6-(1-ethoxyvinyl)-3-methoxypicolinate(1.68 g, 6.66 mmol) in THF (44.4 ml) was added a 2N solution ofhydrochloric acid (6.66 ml, 13.32 mmol). The milky solution was stirredat room temperature overnight. The clear yellow reaction mixture wasconcentrated. The residue was poured into saturated NaHCO3 and extractedwith EtOAc (3×). The combined organic layers were dried over MgSO4,filtered, concentrated and dried in vacuo to afford methyl6-acetyl-4-amino-3-methoxypicolinate (1.55 g, 6.91 mmol, 104% yield) asan orange solid which was used without further purification in the nextstep. ESIMS m/z 223 ([M−H]⁻); ¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H),4.59 (s, 2H), 4.01 (s, 3H), 3.90 (s, 3H), 2.67 (s, 3H).

Example 51 Preparation of methyl4-amino-6-(1-hydroxyethyl)-3-methoxypicolinate

To a 0° C. solution of methyl 6-acetyl-4-amino-3-methoxypicolinate (0.75g, 3.35 mmol) in MeOH (11.15 ml) was added sodium borohydride (0.127 g,3.35 mmol) by portion. The reaction mixture was stirred at roomtemperature (TLC monitoring). After 2 h, the reaction mixture was pouredinto saturated NaHCO3 and extracted with EtOAc (2×) and CH₂Cl₂ (lx). Thecombined organic layers were dried over MgSO4, filtered, concentratedand dried in vacuo to afford methyl4-amino-6-(1-hydroxyethyl)-3-methoxypicolinate (0.548 g, 2.422 mmol,72.4% yield) as a brown oil, which was used without further purificationin the next step. ¹H NMR (400 MHz, CDCl₃) δ 6.72 (s, 1H), 4.76 (q, J=6.4Hz, 1H), 4.52 (s, 2H), 3.96 (s, 3H), 3.94 (s, 1H), 3.86 (s, 3H), 1.45(d, J=6.5 Hz, 3H).

Example 52 Preparation of methyl4-amino-6-(1-fluoroethyl)-3-methoxypicolinate (Compound 83)

To a −10° C. (ice+NaCl) suspension of methyl4-amino-6-(1-hydroxyethyl)-3-methoxypicolinate (0.3 g, 1.326 mmol) inChloroform (6.63 ml) was added dropwise Triflic Acid (0.141 ml, 1.591mmol) followed by Deoxo-Fluor® (0.257 ml, 1.392 mmol). The suspensionwas stirred at −10° C. (LC monitoring). After 2 h, the reaction mixturewas poured into saturated NaHCO3 and extracted with EtOAc (3×). Thecombined organic layers were dried over MgSO4, filtered andconcentrated. The residue was purified by flash column chromatography(ISCO, SiO2 24 g, hexane/EtOAc 100:0 to 0:100 gradient) to afford methyl4-amino-6-(1-fluoroethyl)-3-methoxypicolinate (175 mg, 0.767 mmol, 57.8%yield) as a white solid. ESIMS m/z 227 ([M−H]⁻); ¹H NMR (400 MHz, CDCl₃)δ 6.91 (s, 1H), 5.59 (dq, J=47.6, 6.3 Hz, 1H), 4.53 (s, 2H), 3.97 (s,3H), 3.87 (s, 3H), 1.62 (dd, J=24.6, 6.4 Hz, 3H). ¹⁹F NMR (376 MHz,CDCl₃) δ −176.20.

Example 53 Preparation of 4-amino-6-(1-fluoroethyl)-3-methoxypicolinicacid (Compound 84)

To a solution of methyl 4-amino-6-(1-fluoroethyl)-3-methoxypicolinate(0.125 g, 0.548 mmol) in THF (2.74 ml) and MeOH (2.74 ml) was added a 2Nsolution of sodium hydroxide (0.822 ml, 1.643 mmol). The reactionmixture was stirred at room temperature (LC monitoring). After 4 h, thereaction mixture was acidified with a 2N solution of HCl (1 mL) and thenconcentrated (rotavap). The resulting white solid was dissolved intoDMF+a few drops of water and was purified by preparative HPLC (reversephase, C18 column) to afford4-amino-6-(1-fluoroethyl)-3-methoxypicolinic acid (98 mg, 0.458 mmol,84% yield) as an orange solid. ESIMS m/z 213 ([M−H]⁻); ¹H NMR (400 MHz,DMSO) δ 9.06 (s, 1H), 6.82 (s, 1H), 6.47 (s, 2H), 5.49 (dq, J=47.7, 6.3Hz, 1H), 3.69 (s, 3H), 2.51 (d, J=24.0 Hz, 1H), 1.52 (dd, J=24.5, 6.4Hz, 3H); ¹⁹F NMR (376 MHz, DMSO) δ −171.64.

Example 54 Preparation of methyl6-acetyl-4-[bis(tert-butoxycarbonyl)amino]-3-methoxypyridine-2-carboxylate

To a solution of methyl 6-acetyl-4-amino-3-methoxypicolinate (0.800 g,3.57 mmol) in DCE (11.89 ml) was added di-tert-butyl dicarbonate (2.336g, 10.70 mmol) and N,N-dimethylpyridin-4-amine (0.065 g, 0.535 mmol).The reaction mixture was stirred at room temperature overnight. Themixture was adsorbed onto celite and purified by flash columnchromatography (ISCO, SiO2, 40 g, hexane/EtOAc 100:0 to 0:100 gradient)to afford methyl6-acetyl-4-[bis(tert-butoxycarbonyl)amino]-3-methoxypyridine-2-carboxylate(1.34 g, 3.16 mmol, 88% yield) as a colorless oil. ESIMS m/z 425([M+H]⁺); ¹H NMR (400 MHz, CDCl₃) δ 7.95 (s, 1H), 4.02 (s, 3H), 3.92 (s,3H), 2.71 (s, 3H), 1.42 (s, 18H); ¹³C NMR (101 MHz, CDCl₃) δ 198.07,165.21, 154.04, 150.15, 148.89, 143.72, 142.39, 124.67, 84.30, 62.27,53.11, 27.90, 25.60.

Example 55 Preparation of methyl4-amino-6-(1,1-difluoroethyl)-3-methoxypicolinate (Compound 81)

To a solution of methyl6-acetyl-4-[bis(tert-butoxycarbonyl)amino]-3-methoxypyridine-2-carboxylate(0.7 g, 1.649 mmol) in DCE (3.30 ml) was added Deoxo-Fluor® (1.520 ml,8.25 mmol) and the reaction mixture was stirred at 80° C. overnight. Themixture was allowed to cool down to room temperature and TFA (2 mL) wasadded. The reaction mixture was stirred at room temperature (LCmonitoring). After 12 h, the reaction was completed and extracted withEtOAc (2×). The combined organic layers were dried over MgSO4, filteredand concentrated. The residue was purified by flash columnchromatography (ISCO, SiO2 24 g, hexane/EtOAc 100:0 to 0:100 gradient)to afford methyl 4-amino-6-(1,1-difluoroethyl)-3-methoxypicolinate (336mg, 1.365 mmol, 83% yield) as an orange oil. ESIMS m/z 245 ([M−H]⁻); ¹HNMR (400 MHz, CDCl₃) δ 7.06 (s, 1H), 4.59 (s, 2H), 3.97 (s, 3H), 3.88(s, 3H), 1.98 (t, J=18.7 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −89.99.

Example 56 Preparation of4-amino-6-(1,1-difluoroethyl)-3-methoxypicolinic acid (Compound 82)

To a solution of methyl4-amino-6-(1,1-difluoroethyl)-3-methoxypicolinate (0.229 g, 0.930 mmol)in THF (2.325 ml) and MeOH (2.325 ml) was added a 2N solution of sodiumhydroxide (1.395 ml, 2.79 mmol). The reaction mixture was stirred atroom temperature (LC monitoting). After 4 h, the reaction mixture wasacidified with a 2N solution of HCl (2 mL) and then concentrated(rotavap). The resulting white solid was dissolved into DMF and a fewdrops of water and was purified by preparative HPLC (reverse phase, C18column) to afford 4-amino-6-(1,1-difluoroethyl)-3-methoxypicolinic acid(188 mg, 0.810 mmol, 87% yield) as an orange oil. EIMS m/z 208; ¹H NMR(400 MHz, CDCl₃) δ 6.86 (s, 1H), 6.71 (dd, J=17.6, 10.9 Hz, 1H), 5.98(dd, J=17.6, 1.0 Hz, 1H), 5.42 (dd, J=10.9, 1.0 Hz, 1H), 4.45 (s, 2H),3.97 (s, 3H), 3.87 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 165.94, 152.06,148.02, 143.34, 141.60, 136.73, 118.02, 108.63, 61.49, 52.84.

Example 57 Preparation of Ethyl4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-(methylthio)picolinate(Compound 88)

To a solution of (E)-methyl3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-(((methylsulfonyl)oxy)imino)-1,4,5,6-tetrahydropyridine-2-carboxylate(200 mg, 0.44 mmol) in DMSO (1.4 mL) was added K₂CO₃ (181 mg, 1.3 mmol)followed by sodium thiomethoxide (93 mg, 1.3 mmol). After 10 min thereaction was quenched with 1M HCl solution and then extracted withdiethyl ether. The organics were washed with brine, dried with Na₂SO₄,filtered and purified by silca gel chromatography eluting with 30% Et₂Oin pentane to yielded to afford a brown solid (56 mg, 34%): mp 93-94°C.; ¹H NMR (300 MHz, CDCl₃) δ 7.67 (dd, J=8.6, 7.7 Hz, 1H), 7.22 (m,1H), 7.11 (d, J=1.9 Hz, 1H), 5.16 (s, 2H), 4.47 (q, J=7.1 Hz, 2H), 3.96(d, J=0.9 Hz, 3H), 2.30 (d, J=1.7 Hz, 3H), 1.43 (t, J=7.1 Hz, 3H); ESIMSm/z 369 ([M−H]⁻).

Example 58 Methyl 3-amino-6-(4-chlorophenyl)-4-(methylamino)picolinate(Compound 86)

To a solution (E)-methyl3-chloro-6-(4-chlorophenyl)-4-(((methylsulfonyl)oxy)imino)-1,4,5,6-tetrahydropyridine-2-carboxylate(100 mg, 0.254 mmol) in DMSO (2 mL) was added 2M methanamine in THF (0.8mL, 1.6 mmol). The reaction mixture was stirred at ambient temp for 30min, and then it was diluted with H₂O. The product crashed out ofsolution, and was collect in a Buchner funnel, and dried under vacuum toyielded a brown solid (49 mg, 66%): mp 178-200° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.88 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 6.95 (s, 1H),5.39 (s, 1H), 4.07 (s, 1H), 3.98 (s, 1H), 2.98 (d, J=5.1 Hz, 1H); ESIMSm/z 292 ([M+H]⁺), 290 ([M−H]⁻).

Example 59 Methyl 3-amino-6-(4-chlorophenyl)-4-(dimethylamino)picolinate(Compound 87)

To a solution (E)-methyl3-chloro-6-(4-chlorophenyl)-4-(((methylsulfonyl)oxy)imino)-1,4,5,6-tetrahydropyridine-2-carboxylate(100 mg, 0.254 mmol) in DMSO (2 mL) was added 2M dimethylamine in THF(0.8 mL, 1.6 mmol). The reaction mixture was stirred at ambienttemperature for 30 min, and then it was diluted with H₂O. The resultingmixture was extracted with Et₂O, dried, concentrated and purified bysilica gel chromatography eluting with 20% EtOAc in pentane to afford abrown solid. (45 mg, 58%): mp 153-154° C., ¹H NMR (300 MHz, CDCl₃) δ7.85 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.7 Hz, 2H), 7.34 (s, 1H), 6.06 (s,2H), 3.98 (s, 3H), 2.79 (s, 6H); ESIMS m/z 306 ([M+H]⁺).

Example 60 Ethyl4-amino-6-(4-chloro-2-fluorophenyl)-3-((2,2,2-trifluoroethyl)thio)picolinate(Compound 89)

To a solution of (E)-ethyl3-bromo-6-(4-chloro-2-fluorophenyl)-4-(((methylsulfonyl)oxy)imino)-1,4,5,6-tetrahydropyridine-2-carboxylate(200 mg, 0.43 mmol) in 2,2,2-trifluoroethanethiol (1.4 mL) was addedK₂CO₃ (235 mg, 1.7 mmol). The solution were stirred for 1 h then dilutedwith H₂O, extracted with EtOAc, dried with Na₂SO₄ filtered andconcentrated in vacuo. The residues were purified by silica gelchromatography to afford a yellow solid (130 mg, 75%, 80% pure,remaining 20% is ethyl3-amino-6-(4-chloro-2-fluorophenyl)-4-((2,2,2-trifluoroethyl)thio)picolinate):¹H NMR (400 MHz, CDCl₃) δ 8.02 (m, 1H), 7.23 (m, 1H), 7.16 (m, 16H),5.20 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 3.42 (q, J=10.0 Hz, 2H), 1.44 (t,J=7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −66.36 (s), −113.57 (s); ESIMSm/z 409 ([M+H]⁺), 407 ([M−H]⁻).

Example 61 Preparation of Methyl4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(methylthio)picolinate(Compound 93)

Methyl 4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-iodopicolinate(420 mg, 0.99 mmol) and tri-n-butylmethylthiostannane (530 mg, 1.6 mmol)were dissolved in 5 ml dry DMF. The solution was purged with a nitrogenstream for 10 m, treated with his (triphenylphosphine) palladium (II)chloride (70 mg, 0.01 mmol) and copper (I) iodide (19 mg, 0.01 mmol) andheated to 100° C. After 5 h, an additional 350 mg, 1.0 mmol, of thestannane were added and heating was continued for 8 h more. Aftercooling, the mixture was stirred with 10 ml water and 50 ml ethylacetate and then filtered through a glass wool plug to remove yellowsolids. The organic phase was separated and stirred with 25 ml 10% aq.potassium bifluoride solution for 30 m. After filtration throughdiatomaceous earth, the solution was washed with 10 ml water, 10 ml sat.NaCl, dried (Na₂SO₃) and evaporated. The crude material was purified bysilica gel chromatography using a 0-40% ethyl acetate-hexane gradient.After evaporation of the solvents the oily product was stirred withhexane to produce a white solid which was collected by filtration anddried under vacuum to give 260 mg of the written product as a whitesolid: mp 125-126° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (dd, J=28.9, 9.5Hz, 2H), 7.47 (m, 1H), 5.28 (s, 2H), 3.99 (s, 3H), 2.35 (s, 3H). ¹⁹F NMR(376 MHz, CDCl₃) δ −115.10, −143.40; ESIMS m/z 345 ([M+H]⁺), 343([M−H]⁻).

Example 62 Preparation of Methyl4-amino-6-chloro-5-fluoro-3-(methylthio)picolinate (Compound 74)

Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (1.5 g, 4.6 mmol),tri-n-butylmethylthiostannane (2.5 g, 7.3 mmol), his(triphenylphosphine) palladium (II) chloride (320 mg, 0.46 mmol) andcopper (I) iodide (90 mg, 0.46 mmol) were combined 15 ml dry, deaeratedDMF and heated to 80° C. After 3 h another 2.5 g portion of the stannanewere added and heating was continued for 18 h. After cooling, themixture was stirred with 25 ml 10% potassium bifluoride solution for 20ml. The heterogeneous mixture was stirred with 100 ml ethyl acetate andfiltered through diatomaceous earth to remove curdy solids. Theseparated organic phase was washed twice with 15 ml water, 15 ml sat.NaCl, dried (Na₂SO₃) and evaporated. The product was purified by silicagel chromatography eluting with a 0-25% ethyl acetate-DCM gradient. Thegummy residue was stirred with hexane to produce the written product asa white solid, 800 mg. Mp: 75-77° C. ¹H NMR (400 MHz, CDCl₃) δ 5.35 (s,2H), 3.96 (s, 3H), 2.33 (s, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −138.81.EIMS m/z 250.

Example 63 Preparation of Methyl4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-3-(methylthio)picolinate(Compound 94)

Methyl 4-amino-6-chloro-5-fluoro-3-(methylthio)picolinate (300 mg, 1.2mmol),2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(450 mg, 1.6 mmol) Cesium fluoride (370 mg, 2.4 mmol) and his(triphenylphosphine) palladium (II) chloride (84 mg, 0.12 mmol) werecombined in 5 ml 1:1 acetonitrile-water and heated in a microwavereactor at 115° C. for 30 m. The mixture was shaken with 30 ml ethylacetate and 10 ml water. The org. phase was washed with 10 ml sat. NaCl,dried (Na₂SO₃) and evaporated. The residue was chromatographed on silicawith a 0-40% ethyl acetate-hexane gradient. The gummy material wasstirred with hexane to produce the written compound as a white solid, 60mg. Mp: 113-117° C. ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.24 (m, 2H), 5.31(s, 2H), 3.98 (d, J=1.1 Hz, 3H), 3.96 (s, 3H), 2.32 (s, 3H). 19F NMR(376 MHz, CDCl3) δ −127.97, −128.06, −140.43, −140.52. ESIMS m/z 375([M+H]⁺), 373 ([M−H]⁻).

Example 64 Preparation of methyl4-amino-3-fluoro-5,6′-dimethoxy-[2,3′-bipyridine]-6-carboxylate(Compound 75)

To a tube, methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (500 mg,2.131 mmol), (6-methoxypyridin-3-yl)boronic acid (391 mg, 2.56 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78 mg,0.107 mmol) and Cesium Fluoride (647 mg, 4.26 mmol) were charged assolids. The tube was sealed and charged with inert atmosphere. Thesolids were then diluted with Dioxane (5700 μl) and Water (1400 μl). Theresulting suspension was heated to 85° C. for 18 hrs. The reactionsolution was poured in to a brine solution. The aqueous phase wasextracted with EtOAc (3×25 mL). The combined organic layers were driedover MgSO₄, filtered and concentrated under vacuum. The product waspurified (flash chromatography: silica, 5-50% EtOAc in Hex 16 CV; C₁₈5-100% ACN in H₂O 16 CV) to yield methyl4-amino-3-fluoro-5,6′-dimethoxy-[2,3′-bipyridine]-6-carboxylate (186 mg,0.605 mmol, 28.4% yield). ESIMS for m/z 308 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 3.77 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H), 6.53 (s, 2H), 6.95(dd, J=8.6, 0.8 Hz, 1H), 8.10 (ddd, J=8.6, 2.4, 1.1 Hz, 1H), 8.58 (t,J=2.0 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −141.20.

Example 65 Preparation of4-amino-3-fluoro-5,6′-dimethoxy-[2,3′-bipyridine]-6-carboxylic acid(Compound 78)

To a solution of methyl4-amino-3-fluoro-5,6′-dimethoxy-[2,3′-bipyridine]-6-carboxylate (100 mg,0.325 mmol) in THF (1.0 mL), MeOH (1.000 mL), and Water (0.500 mL),lithium hydroxide hydrate (60 mg, 1.430 mmol) was added as a solid. Thesolution was stirred at room temperature for 18 hrs. The reactionsolution was then concentrated under vacuum to dryness. The resultingsolid was suspended in H₂O and the pH was adjusted to 3.8, forming appt. The suspension was extracted with EtOAc (3×25 mL). The combinedorganic layers were dried over MgSO₄, filtered and concentrated undervacuum to yield4-amino-3-fluoro-5,6′-dimethoxy-[2,3′-bipyridine]-6-carboxylic acid(80.1 mg, 0.273 mmol, 84% yield).). ESIMS for m/z 294 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 3.78 (s, 3H), 3.92 (s, 3H), 6.47 (s, 2H), 6.95 (dd,J=8.7, 0.8 Hz, 1H), 8.15 (ddd, J=8.7, 2.4, 1.1 Hz, 1H), 8.61 (t, J=2.1Hz, 1H), 13.02 (s, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −141.78.

Example 66 Preparation of methyl4-amino-6′-cyclopropyl-3-fluoro-5-methoxy-[2,3′-bipyridine]-6-carboxylate(Compound 76)

To a tube, methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (500 mg,2.131 mmol) (˜90% pure), (6-cyclopropylpyridin-3-yl)boronic acid (417mg, 2.56 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78 mg,0.107 mmol), and Cesium Fluoride (647 mg, 4.26 mmol) were charged assolids. The tube was sealed and charged with inert atmosphere. Thesolids were then diluted with Dioxane (5.7 ml) and Water (1.4 ml). Theresulting suspension was heated to 85° C. for 18 hrs. The reactionsolution was poured in to a brine solution. The aqueous phase wasextracted with EtOAc (3×25 mL). The combined organic layers were driedover MgSO₄, filtered and concentrated under vacuum. The product waspurified (flash chromatography: silica, 5-50% EtOAc in Hex 16 CV; C₁₈5-100% ACN in H₂O 16 CV) to yield methyl4-amino-6′-cyclopropyl-3-fluoro-5-methoxy-[2,3′-bipyridine]-6-carboxylate(0.218 g, 0.687 mmol, 32.2% yield). ESIMS for m/z 318 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 0.99 (tt, J=7.6, 2.7 Hz, 4H), 2.17 (tt, J=7.8, 5.1Hz, 1H), 3.77 (s, 3H), 3.86 (s, 3H), 6.55 (s, 2H), 7.42 (d, J=8.9 Hz,1H), 8.00 (ddd, J=8.2, 2.3, 1.2 Hz, 1H), 8.77 (t, J=2.0 Hz, 1H). ¹⁹F NMR(376 MHz, DMSO-d₆) δ −141.19.

Example 67 Preparation of4-amino-6′-cyclopropyl-3-fluoro-5-methoxy-[2,3′-bipyridine]-6-carboxylicacid (Compound 77)

To a solution of methyl4-amino-6′-cyclopropyl-3-fluoro-5-methoxy-[2,3′-bipyridine]-6-carboxylate(100 mg, 0.315 mmol) in THF (1.00 mL), MeOH (1.000 mL), and Water (0.500mL), lithium hydroxide hydrate (65 mg, 1.549 mmol) was added as a solid.The reaction was allowed to stir at room temperature for 18 hrs. Thereaction solution was then concentrated under vacuum to dryness. Theresulting solid was suspended in H₂O and the pH was adjusted to 4.0,forming a ppt. The suspension was extracted with EtOAc (3×25 mL). Thecombined organic layers were dried over MgSO₄, filtered and concentratedunder vacuum to yield4-amino-6′-cyclopropyl-3-fluoro-5-methoxy-[2,3′-bipyridine]-6-carboxylicacid (50.0 mg, 0.165 mmol, 52.3% yield). ESIMS for m/z 304 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 0.92-1.06 (m, 4H), 2.17 (tt, J=7.8, 5.1 Hz,1H), 3.78 (s, 3H), 6.49 (s, 2H), 7.42 (dd, J=8.3, 0.9 Hz, 1H), 8.05(ddd, J=8.2, 2.2, 1.1 Hz, 1H), 8.81 (t, J=2.0 Hz, 1H), 13.03 (s, 1H).¹⁹F NMR (376 MHz, DMSO-d₆) δ −141.73.

Example 68 Preparation of 4-amino-5-fluoro-3-methoxy-6-vinylpicolinicacid (Compound 95)

To a solution of methyl 4-amino-5-fluoro-3-methoxy-6-vinylpicolinate(140.0 mg, 0.619 mmol) in THF (1.2 mL), MeOH (1.200 mL), Water (0.600mL), lithium hydroxide hydrate (78 mg, 1.857 mmol) was charged as asolid. The reaction was allowed to stir at room temperature for 18 hrs.The reaction was concentrated to dryness. The resulting residue wasdiluted with 2 N HCl and MeOH. The product was purified (C₁₈ 10-80% ACNin H₂O 12 CV) to yield 4-amino-5-fluoro-3-methoxy-6-vinylpicolinic acid(79 mg, 0.372 mmol, 60.2% yield). ESIMS for m/z 213 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 3.73 (s, 3H), 5.50 (dd, J=11.0, 2.2 Hz, 1H), 6.20 (dd,J=17.3, 2.2 Hz, 1H), 6.35 (s, 2H), 6.83 (ddd, J=17.3, 10.9, 1.7 Hz, 1H),12.98 (s, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −145.09.

TABLE 1 Structures of Compounds in Examples Com- Prepared as pounddescribed in Number Structure Example: Precursor 1

 9 Methyl 4,6-dichloro- 3-methoxypicolinate 2

10 Compound 1 3

12 Methyl 4-acetamido- 6-(4-chloro-2-fluoro- 3-methoxyphenyl)-3-hydroxypicolinate 4

12 Methyl 4-acetamido- 6-(4-chloro-2- fluorophenyl)-3- hydroxypicolinate5

13 Compound 3 6

13 Compound 4 7

14 methyl 4-amino-6- bromo-3- methoxypicolinate 8

19 2-Chloro-6-(4-chloro- 2-fluoro-3- methoxyphenyl)-3-(difluoromethoxy)pyri- din-4-amine 9

19 2-Chloro-6-(4-chloro- 2-fluoro-3- methoxyphenyl)-3-(difluoromethoxy)pyri- din-4-amine 10

26 methyl 4-amino-6- chloro-5-fluoro-3- iodopicolinate 11

29 Methyl 4-amino-5- fluoro-3- iodopicolinate 12

30 Compound 10 13

31 Compound 12 14

32 Compound 10; (2- fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)trimethyl- silane 15

33 Compound 10; (2,3- difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolane-2- yl)phenyl)trimethyl- silane 16

33 Compound 10 17

34 Compound 10; (2,5- Difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)trimethyl- silane 18

34 Compound 10; (3- fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)- phenyl)trimethylsilane 19

35 Compound 15 20

35 Compound 17 21

35 Compound 14 22

35 Compound 18 23

36 Compound 16 24

36 Compound 15 25

36 Compound 17 26

36 Comopund 18 27

36 Compound 14 28

42 Compound 24 29

37 Compound 10 30

38 Compound 29 31

39 Compound 10 32

39 Compound 10 33

40 Compound 10 34

40 Compound 10 35

40 Compound 10 36

40 Compound 10 37

40 Compound 10 38

40 Compound 10 39

40 Compound 10 40

40 Compound 10 41

40 Compound 10 42

40 Compound 10 43

40 Compound 10 44

41 methyl 4-amino-6- bromo-5-chloro-3- methoxypicoliate 45

42 Compound 5 46

42 Compound 7 47

42 Compound 31 48

42 Methyl 4-amino-6-(4- chloro-2,3- difluorophenyl)-5- fluoro-3-methoxypicolinate 49

42 Compound 32 50

42 Compound 35 51

42 Compound 10 52

42 Compound 36 53

42 Compound 37 54

42 Compound 19 55

42 Compound 23 56

42 Compound 38 57

42 Compound 39 58

42 Compound 13 59

42 Compound 20 60

42 Compound 25 61

42 Compound 22 62

42 Compound 26 63

42 Compound 40 64

42 Compound 9 65

42 Compound 33 66

43 Compound 45 67

44 (E)-ethyl 3-bromo-6- (4-chloro-2- fluorophenyl)-4-(((methylsulfonyl)oxy) imino)-1,4,5,6- tetrahydropicolinate 68

44 (E)-ethyl 3-bromo-6- (4-chloro-2- fluorophenyl)-4-(((methylsulfonyl)oxy) imino)-1,4,5,6- tetrahydropicolinate 69

40 Compound 10 70

42 Compound 67 71

42 Compound 69 72

42 Compound 93 73

42 Compound 74 74

62 methyl 4-amino-6- chloro-5-fluoro-3- iodopicolinate 75

64 Compound 10 76

66 Compound 10 77

67 Compound 76 78

65 Compound 75 79

65 Compound 80 80

66 Compound 10 81

55 methyl 6-acetyl-4- [bis(tert- butoxycarbonyl)amino]- 3-methoxypyridin-2- carboxylate 82

56 Compound 81 83

52 methyl 4-amino-6-(1- hydroxyethyl)-3- methoxypicolinate 84

53 Compound 83 85

45 Methyl 4-amino-6- bromo-3- methoxypicolinate 86

58 (E)-methyl 3-chloro- 6-(4-chlorophenyl)-4- (((methylsulfonyl)oxy)imino)-1,4,5,6- tetrahydropyridine-2- carboxylate 87

59 (E)-methyl 3-chloro- 6-(4-chlorophenyl)-4- (((methylsulfonyl)oxy)imino)-1,4,5,6- tetrahydropyridine-2- carboxylate 88

57 (E)-methyl 3-chloro- 6-(4-chloro-2-fluoro- 3-methoxyphenyl)-4-(((methylsulfonyl)oxy) imino)-1,4,5,6- tetrahydropyridine-2- carboxylate89

60 (E)-ethyl 3-bromo-6- (4-chloro-2- fluorophenyl)-4-(((methylsulfonyl)oxy) imino)-1,4,5,6- tetrahydropyridine-2- carboxylate91

28 methyl 4-amino-6-(4- chloro-3- fluorophenyl)-5- fluoropicolinate 92

48 methyl 4-[bis(tert- butoxycarbonyl)amino]- 6-formyl-3-methoxypyridine-2- carboxylate 93

61 Compound 92 94

63 Compound 74 95

68 Compound 12

TABLE 2 Analytical Data for Compounds in Table 1 Compound ¹H NMR OtherNMR (field Number Appearance mp (° C.) ESIMS¹ m/z (field strength,solvent) δ strength, solvent) δ 1 White Solid 78-79 EIMS m/z (400 MHz,CDCl₃) 6.76 216 (s, 1H), 4.84 (s, 2H), 3.95 (s, 3H), 3.87 (s, 3H) 2White Solid 119-121 EIMS m/z (400 MHz, CDCl₃) 5.04 250 (s, 2H), 3.97 (s,3H), 3.93 (s, 3H) 3 Yellow Oil 383 (400 MHz, CDCl₃) 8.93 ([M+H]⁺) (d, J= 1.6 Hz, 1H), 8.06 (s, 1H), 7.56 (dd, J = 8.5, 7.7 Hz, 1H), 7.23 (dd, J= 8.6, 1.7 Hz, 1H), 4.01 (s, 3H), 3.99 (d, J = 1.0 Hz, 3H), 3.98 (s,3H), 2.29 (s, 3H) 4 Yellow Oil 353 (400 MHz, CDCl₃) 8.96 ([M+H]⁺) (d, J= 1.5 Hz, 1H), 7.99 (s, 1H), 7.89 (t, J = 8.4 Hz, 1H), 7.23 (ddd, J =8.4, 2.1, 0.6 Hz, 1H), 7.19 (dd, J = 10.7, 2.0 Hz, 1H), 4.02 (s, 3H),3.99 (s, 3H), 2.29 (s, 3H) 5 Off-White 114-118 341 (400 MHz, CDCl₃) 7.61Solid ([M+H]⁺), (dd, J = 8.5, 7.8 Hz, 1H), 339 ([M−H]⁻) 7.22 (dd, J =8.6, 1.8 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H), 4.54 (s,1H), 3.98 (s, 2H),3.96 (d, J = 0.8 Hz, 2H), 3.92 (s, 2H) 6 White Solid 139-144 311 (400MHz, CDCl₃) 7.96 ([M+H]⁺) (t, J = 8.5 Hz, 1H), 7.25 (d, J = 1.3 Hz, 1H),7.22 (dd, J = 2.0, 0.6 Hz, 1H), 7.15 (dd, J = 11.1, 2.0 Hz, 1H), 6.07(s, 2H), 3.99 (s, 3H), 3.97 (s, 3H) 7 Brown Oil 291 (300 MHz, CDCl₃)7.90 − ([M−H]⁻) 7.81 (m, 2H), 7.46 − 7.36 (m, 2H), 7.12 (s, 1H), 4.56(s, 2H), 4.01 (s, 3H), 3.92 (s, 3H) 8 White Solid 391 (300 MHz, CDCl₃)7.66 ¹⁹F NMR (376 ([M+H]⁺), (dd, J = 8.6, 7.7 Hz, 1H), MHz, CDCl₃) 3897.28-7.24 (m, 1H), 7.22 −79.74, −132.19 ([M−H]⁻) (d, J = 1.7 Hz, 1H),6.72 (t, J = 75.1 Hz, 1H), 4.73 (s, 2H), 4.46 (q, J = 7.1 Hz, 2H), 3.97(d, J = 0.8 Hz, 3H), 1.42 (t, J = 7.2 Hz, 3H) 9 White Solid 162-164 375(300 MHz, DMSO-d₆) ([M−H]⁻) 7.63 (m, 1H), 7.23 (m, 1H), 6.75 (t, J = 57Hz, 1H), 4.74 (s, 2H), 3.975 (d, J = 3 Hz, 3H) 10 Purple Solid EIMS m/z(400 MHz, CDCl₃) 4.67 ¹⁹F NMR (376 234 (s, 2H), 3.96 (s, 3H), 3.93 MHz,CDCl₃) (s, 3H) −135.15 (s) 11 Red Semi- 347.81 (400 MHz, CDCl₃) 7.83 ¹⁹FNMR (376 Solid ([M−H]⁻) 7.63 (m, 4H), 4.89 (s, MHz, DMSO-d6) 2H), 4.08(s, 3H) −59.91, −59.93, −59.94, −115.72, −115.75, −140.39 12 Yellow 227(400 MHz, CDCl₃) δ.88 ¹⁹F NMR (376 Liquid ([M+H]+) (ddd, J = 17.5, 11.1,1.4 MHz, CDCl₃) Hz, 1H), 6.33 (dd, J = −143.2 17.5, 1.6 Hz, 1H), 5.57(ddd, J = 11.1, 1.6, 0.7 Hz, 1H), 4.47 (s, 2H), 3.97 (s, 3H), 3.91 (s,3H) 13 White Solid 110.5-113.0 EIMS m/z (400 MHz, CDCl₃) 4.41 ¹³C NMR(101 228 (s, 2H), 3.96 (s, 3H), 3.90 MHz, CDCl₃) (s, 3H), 2.81 (qd, J =7.6, 146.2, 144.2, 2.7 Hz, 2H), 1.26 (t, J = 136.8, 136.1, 7.6 Hz, 3H)61.5, 52.7, 25.3, 12.9; ¹⁹F NMR (376 MHz, CDCl₃) −142.6 14 Light Pink367 (400 MHz, CDCl₃) 7.66 ¹⁹F NMR (376 Oil ([M+H]+) (d, J = 7.6 Hz, 1H),7.55 MHz, CDCl₃) (d, J = 9.8 Hz, 1H), 7.46 −100.72, (dd, J = 7.6, 5.9Hz, 1H), −140.12 4.57 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 0.33 (s, 9H)15 White Solid 123-125 383.20 (400 MHz, CDCl₃) 7.32 ¹⁹F NMR (376([M−H]⁻) (ddd, J = 7.6, 5.5, 1.1 Hz, MHz, CDCl₃) 1H), 7.20 (ddd, J =7.7, −127.39, 4.5, 1.4 Hz, 1H), 4.60 (s, −127.45, 2H), 3.98 (s, 3H),3.96 (s, −127.46, 3H), 0.41 − 0.28 (m, 9H) −137.48, −137.56, −140.78,−140.85, −140.86, −140.92 16 Red Solid 349.59 (400 MHz, DMSO-d₆) ¹⁹F NMR(376 ([M+H]⁺) 7.80 − 7.70 (m, 2H), 7.63 MHz, DMSO-d₆) (d, J = 8.2 Hz,2H), 6.49 −141.15 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H) 17 Yellow Solid137-139 384 (400 MHz, CDCl₃) 7.23 ¹⁹F NMR (376 ([M]⁺) (dd, J = 7.9, 5.1Hz, 1H), MHz, CDCl₃) 7.12 (dd, J = 9.3, 4.0 Hz, −107.12, 1H), 4.60 (s,2H), 3.97 (s, −121.88, 3H), 3.97 (s, 3H), 0.33 −137.27 (d, J = 0.8 Hz,9H) 18 Yellow Solid 127-129 367 (400 MHz, CDCl₃) 7.56 ¹⁹F NMR (376([M+H]⁺) (t, J = 7.2 Hz, 1H), 7.37 MHz, CDCl₃) (dd, J = 7.5, 0.7 Hz,1H), −116.17, 7.26 (dd, J = 10.1, 0.8 −137.36 Hz, 1H), 4.57 (s, 2H),3.97 (s, 3H), 3.96 (s, 3H), 0.28 (s, 9H) 19 White Solid 392.06 (400 MHz,DMSO-d₆) ¹⁹F NMR (376 ([M+H]⁺) 7.67 (ddd, J = 8.3, 6.3, MHz, DMSO-d6)1.7 Hz, 1H), 7.40 − 7.27 −131.44, (m, 1H), 6.68 (s, 2H), −131.45, 3.84(s, 3H), 3.79 (s, 3H) −131.46, −131.50, −131.50, −131.51, −131.52,−136.12, −136.14, −136.19, −136.20, −136.22, −136.26, −136.28, −138.65,−138.72 20 Orange Solid 116-118 391 (400 MHz, CDCl₃) 7.40 ¹⁹F NMR (376([M]⁺) (d, J = 6.0, 8.4 Hz, 1H), MHz, CDCl₃) 7.37 (d, J = 6.0, 8.4 Hz,−113.12, 1H), 4.62 (s, 2H), 3.98 (s, −117.61, 3H), 3.97 (s, 3H) −137.2221 White Solid 375 (400 MHz, CDCl₃) 7.75 ¹⁹F NMR (376 ([M+H]⁺) (d, J =9.6 Hz, 1H), 7.65 − MHz, CDCl₃) 372 7.57 (m, 2H), 4.59 (s, −107.19,([M−H]⁻) 2H), 3.99 (s, 3H), 3.96 (s, −139.83 3H) 22 Orange 373 (400 MHz,CDCl₃) 7.48 ¹⁹F NMR (376 Gummy Oil ([M]⁺) (t, J = 7.8 Hz, 1H), 7.40 MHz,CDCl₃) (dd, J = 8.3, 1.5 Hz, 1H), −111.54, 7.34 (dd, J = 9.4, 1.5 Hz,−137.36 1H), 4.60 (s, 2H), 3.97 (s, 6H) 23 Orange Solid 403.61 (400 MHz,DMSO-d₆) ¹⁹F NMR (376 ([M+H]⁺) 7.86 (d, J = 8.5 Hz, 2H), MHz, DMSO-d6)7.65 − 7.53 (m, 2H), 6.54 −140.64 (s, 2H), 3.86 (s, 3H), 3.77 (s, 3H) 24White Solid EIMS m/z (400 MHz, DMSO-d₆) ¹⁹F NMR (376 439.33 7.84 − 7.70(m, 1H), 7.23 MHz, DMSO-d6) ([M+H]⁺) 7.12 (m, 1H), 6.66 (s, −119.00,2H), 3.84 (s, 3H), 3.78 (s, −119.06, 3H) −136.73, −136.80, −136.81,−136.87, −138.61, −138.69 25 White Solid 127-129 439 (400 MHz, CDCl₃)7.54 ¹⁹F NMR (376 ([M+H]⁺) (dd, J = 8.5, 5.0 Hz, 1H), MHz, CDCl₃) 7.32(dd, J = 7.6, 5.8 Hz, −100.21, 1H), 4.62 (s, 2H), 3.98 (s, −118.29, 3H),3.97 (s, 3H) −137.17 26 Brown Solid dec 421 (400 MHz, CDCl₃) 7.60 ¹⁹FNMR (376 ([M+H]⁺) (dd, J = 8.2, 1.6 Hz, 1H), MHz, CDCl₃) 7.52 (dd, J =9.2, 1.6 Hz, −111.86, 1H), 7.32 (t, J = 7.8 Hz, −137.30 1H), 4.59 (s,2H), 3.97 (s, 6H) 27 Sticky 421 (400 MHz, CDCl₃) 7.82 ¹⁹F NMR (376Orange Solid ([M+H]⁺) , (dd, J = 8.3, 6.5 Hz, 1H), MHz, CDCl₃) 420 7.68(ddd, J = 9.3, 1.9, −93.82, ([M+H]⁺) 1.1 Hz), 7.50 (dt, J = −139.71 8.3,1.7 Hz, 1H), 4.60 (s, 2H), 3.99 (s, 3H), 3.96 (s, 3H) 28 Off-White145-147 425.22 (400 MHz, DMSO-d₆) ¹⁹F NMR (376 Solid ([M+H]⁺) 13.15 (s,1H), 7.86 − 7.71 MHz, DMSO-d6) (m, 1H), 7.21 (ddd, J = −119.08, 8.3,6.5, 1.7 Hz, 1H), −119.14, 6.59 (s, 2H), 3.79 (s, 3H) −136.61, −136.67,−136.69, −136.75, −139.25, −139.33 29 Tan Solid 305 (400 MHz, CDCl₃)10.08 ¹⁹F NMR (376 ([M+H]⁺), (s, 1H), 8.09 (dd, J = 8.3, MHz, CDCl3) 303([M−H]⁻) 1.5 Hz, 2H), 8.03 − 7.93 −139.69 (m, 2H), 4.62 (s, 2H), 4.00(s, 3H), 3.98 (s, 3H) 30 Off-White 301 (400 MHz, CDCl3) 7.93 − ¹⁹F NMR(376 Solid ([M+H]⁺), 7.85 (m, 2H), 7.62 − MHz, CDCl₃) 299 ([M−H]⁻) 7.53(m, 2H), 4.57 (s, −139.97 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.15 (s, 1H)31 Tan Solid 93-94 311 (400 MHz, acetone-d6) ([M+H]⁺) , 7.96 (dd, J =8.8, 1.4 Hz, 309 ([M−H]⁻) 1H), 7.57 − 7.49 (m, 1H), 5.93 (s, 1H), 3.92(s, 1H), 3.91 (s, 1H) 32 Pinkish Solid 109-110 EIMS m/z (400 MHz,acetone-d6) 328 7.93 − 7.78 (m, 2H), 7.72 − 7.61 (m, 1H), 5.99 (s, 1H),3.93 (s, 3H), 3.92 (s, 3H) 33 Sticky 375 (400 MHz, CDCl₃) 7.53 − ¹⁹F NMR(376 Brown- ([M+1-]⁺), 7.46 (m, 1H), 7.29 (dt, MHz, CDCl3) Orange Solid373 T = 8.4, 1.1 Hz, 1H), 6.39 − −113.81, ([M−H]⁻) 6.03 (m,1H), 4.61 (s,−113.87, 2H), 3.97 (d, J = 2.1 Hz, −113.90, 6H), 1.85 − 1.68 (m, 3H)−113.95, −137.05, −137.14, −175.47, −175.52 34 Off-White 133.5- 360 (400MHz, CDCl₃) 7.27 ¹⁹F NMR (376 Solid 135.5 ([M+H]⁺) , 7.21 (m, 2H), 4.60(s, MHz, CDCl3) 358 2H), 3.98 − 3.97 (m, 9H) −128.8, −137.4 ([M−H]⁻) 35Off-White 97-99 343.24 (400 MHz, CDCl₃) 8.03 ¹⁹F NMR (376 Solid ([M−H]⁻)(d, J = 8.1 Hz, 2H), 7.76 − MHz, CDCl₃) 7.66 (m, 2H), 4.61 (s, −62.71,2H), 3.99 (s, 3H), 3.97 −140.31 (d, J = 3.5 Hz, 3H) 36 White Solid141-143 295.49 (400 MHz, DMSO-d₆) ¹⁹F NMR (376 ([M+H]⁺) , 7.92-7.75 (m,2H), 7.32 MHz, DMSO-d₆) 293.04 (t, J = 8.9 Hz, 2H), 6.52 −112.76,([M−H]⁻) (s, 2H), 3.86 (s, 3H), 3.77 −141.18 (s, 3H) 37 Off-White110-112 321.1 (400 MHz, DMSO-d₆) ¹⁹F NMR (376 Solid ([M+H]) 7.38-7.25(m, 2H), 7.02 MHz, DMSO-d₆) (d, J = 8.1 Hz, 1H), 6.45 −140.87 (s, 2H),6.09 (s, 2H), 3.85 (s, 3H), 3.76 (s, 3H) 38 White Solid 139-141 379.57(400 MHz, DMSO-d₆) ¹⁹F NMR (376 ([M+H]⁺) , 7.75 (t, J = 7.2 Hz, 1H),MHz, DMSO-d6) 377.49 ([M − 7.60 (t, J = 7.2 Hz, 1H), −59.83 (d, J = 12.5Hz), H]⁻) 6.75 (s, 2H), 3.85 (s, 3H), −136.46 − −138.21 (m), 3.80 (s,3H) −138.55 (d, J = 28.4 Hz), −140.24 − −141.37 (m) 39 Pink Solid120-123 347 (400 MHz, CDCl₃) 7.42 ¹⁹F NMR (376 ([M+H]⁺), (dd, J = 8.9,6.1 Hz, 1H), MHz, CDCl₃) 346 ([M−H]⁻) 7.23 (dd, J = 8.8, 6.0 Hz, −117.4,−120.8, 1H), 4.63 (s, 2H), 3.98 −137.2 (m, 6H) 40 White Solid 130-132344 (400 MHz, CDCl₃) 9.25 ¹⁹F NMR (376 ([M−H]⁻) (s, 1H), 8.43 (d, J =8.2 MHz, CDCl₃) Hz, 1H), 7.78 (d, J = 8.2 −67.96, Hz, 1H), 4.67 (s, 2H),−140.19, 4.00 (s, 3H), 3.98 (s, 3H) −140.20, −140.21 41 Yellow- 302 (400MHz, CDCl₃) 8.08- ¹⁹F NMR (376 Orow-Solid ([M+H]⁺) 8.00 (m, 2H), 7.78-MHz, CDCl₃) 300 7.69 (m, 2H), 4.62 (s, −139.91 ([M−H]⁻) 2H), 3.99 (s,3H), 3.97 (s, 3H) 42 Tan Solid 339 (400 MHz, CDCl₃) 7.07 ¹⁹F NMR (376([M+H]⁺), (dd, J = 8.2, 6.4 Hz, 1H), MHz, CDCl₃) 337 ([M−H]⁻) 6.75 (dd,J = 8.2, 0.6 Hz, −137.74, 1H), 6.08 (s, 2H), 4.56 (s, −139.47 2H), 3.97(s, 3H), 3.96 (s, 3H) 43 Brown Solid 113-115 372.44 (400 MHz, DMSO-d₆)¹⁹F NMR (376 ([M+H]⁺) , 7.38 (dd, J = 8.4, 1.3 Hz, MHz, DMSO-d₆) 370.491H), 7.22 (dd, J = 8.4, −120.48, ([M−H]⁻) 7.3 Hz, 1H), 6.58 (s, 2H),−120.55, 3.84 (s, 3H), 3.78 (s, 3H) −138.35, −138.42 44 White Solid139-141 326.00 (400 MHz, DMSO-d₆) ([M−H]⁻) 7.60-7.54 (m, 2H), 7.54 7.47(m, 2H), 6.68 (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H) 45 White Solid 143-146345 (400 MHz, CDCl₃) 7.30 ¹⁹F NMR (376 ([M+H]⁺), (dd, J = 8.5, 1.6 Hz,1H), MHz, CDCl3) 343 7.19 (dd, J = 8.4, 6.8 Hz, −128.66, ([M−H]⁻) 1H),4.83 (s, 2H), 4.07 (s, −128.74, 3H), 4.02 (d, J = 1.1 Hz, −134.93, 3H)−135.01 46 Off-white 165 279 (300 MHz, DMSO-d₆) Solid ([M+H]⁺), 7.88 (m,2H), 7.48 (d, J = 277 8.58.5 Hz, 2H), 7.18 (s, 1H), ([M−H]⁻) 6.30 (s,2H), 3.70 (s, 3H) 47 White Solid 297 (400 MHz, DMSO-d₆) ([M+H]⁺), 13.06(s, 1H), 7.86 (dd, J = 295 8.6, 1.3 Hz, 2H), 7.59 ([M−H]⁻) 7.51 (m, 2H),6.46 (s, 2H), 3.78 (d, J = 5.5 Hz, 3H) 48 Off-White 151 333 (400 MHz,acetone-d₆) Solid ([M+H]⁺), 7.58 − 7.48 (m, 2H), 6.22 331 (s, 1H), 3.97(s, 3H) ([M−H]⁻) 49 Off-White 137 315 (400 MHz, DMSO-d₆) Solid ([M+H]⁺),7.89 − 7.82 (m, 1H), 7.72 313 (d, J = 4.9 Hz, 1H), 6.57 ([M−H]⁻) (s,1H), 3.78 (s, 3H) 50 White Solid 135-137 330.234 (400 MHz, CDCl₃) 7.97¹⁹F NMR (376 ([M+H]⁺), (d, J = 8.1 Hz, 2H), 7.77 MHz, CDCl₃) 329.98 (d,J = 8.2 Hz, 2H), 4.86 −62.81, ([M−H]⁻) (s, 2H), 4.07 (s, 3H), 1.67−137.90 (s, 1H) 51 Off-White 221.46 (400 MHz, DMSO-d₆) ¹⁹F NMR (376Solid ([M+H]⁺) 13.22 (d, J = 68.3 Hz, MHz, DMSO-d₆) 1H), 6.75 (s, 2H),3.74 (s, −137.53 (s) 3H) 52 Off-White 149-151 281.8 (400 MHz, DMSO-d₆)¹⁹F NMR (376 Solid ([M+H]+), 12.97 (s, 1H), 7.88 (dd, J = MHz, DMSO-d₆)279.7 7.6, 5.7 Hz, 2H), 6.45 −112.85, ([M−H]⁻) (s, 2H), 3.78 (s, 3H)−141.74 53 White Solid 223-225 308. 1 (400 MHz, DMSO-d⁶) ¹⁹F NMR (376([M+H]⁺) 7.32 (d, J = 9.0 Hz, 2H), MHz, DMSO-d₆) 6.97 (d, J = 7.9 Hz,1H), −147.68 6.06 (s, 2H), 5.70 (s, 2H), 3.74 (s, 3H) 54 White Solid375.9 (400 MHz, DMSO-d₆) ¹⁹F NMR (376 ([M−H]⁻) 7.67 (ddd, J = 8.3, 6.3,MHz, DMSO-d₆) 1.7 Hz, 1H), 7.37 (ddd, J = −131.62 8.6, 6.9, 1.9 Hz, 1H),(ddd, J = 22.9, 6.56 (s, 2H), 3.79 (s, 3H), 6.3, 1.7 Hz), −135.83 −−136.35 (m), −3.37 (s, 2H) 139.80 (d, J = 27.9 Hz) 55 Orange Solid387.87 (400 MHz, DMSO-d6) ¹⁹F NMR (376 ([M−H]⁻) 12.99 (d, J = 70.4 Hz,MHz, DMSO-d₆) 1H), 7.96-7.77 (m, 2H), −141.18 (s) 7.71-7.54 (m, 2H),6.46 (s, 2H), 3.77 (s, 3H) 56 White Solid 133-135 367.2 (400 MHz,DMSO-d₆) ¹⁹F NMR (376 ([M+H]⁺), 13.14 (d, J = 72.7 Hz, MHz, DMSO-d₆)1H), 7.76 (t, J = 7.2 Hz, −59.81 (d, J = 1H), 7.61 (dd, J = 19.3, 12.6Hz), 11.7 Hz, 1H), 6.66 (s, −137.11 − 2H), 3.80 (s, 3H) −138.15 (m),−139.22 (d, J = 29.8 Hz), −140.65 (dt, J = 25.2, 12.5 Hz) 57 White Solid153.5- 333 (400 MHz, CDCl₃) 7.36 ¹⁹F NMR (376 155.0 ([M+H]⁺), (dd, J =8.7, 6.0 Hz, 1H), MHz, CDCl₃) 331 7.30 (dd, J = 9.0, 5.9 Hz, −117.2,−120.2, ([M−H]⁻) 1H), 4.86 (s, 2H), 4.07 (s, 3H) −135.0 58 White Solid148.5-150.5 215 (400 MHz, DMSO-d₆) ¹⁹F NMR (376 ([M+H]⁺) 6.26 (s, 2H),3.71 (s, 3H), MHz, DMSO-d₆) 2.64 (qd, J = 7.6, 2.6 Hz, −139.6 2H), 1.15(t, J = 7.6 Hz, 3H) 59 Yellow Solid 147-148 376 (400 MHz, DMSO-d₆) ¹⁹FNMR (376 ([M−H]⁻) 7.88 (dd, J = 9.0, 5.7 Hz, MHz, DMSO-d₆) 1H), 7.59(dd, J = 8.7, −113.74, 6.1 Hz, 1H), 6.58 (s, 2H), −117.64, 3.78 (s, 3H)−138.88 60 White Solid 132-134 425 (400 MHz, DMSO-d₆) ¹⁹F NMR (376 ([M+H]⁺) 7.91 (dd, J = 8.8, 5.1 Hz, MHz, DMSO-d₆) 1H), 7.44 (dd, J = 8.0,−101.29, 5.9 Hz, 1H), 6.57 (s, 2H), −118.82, 3.78 (s, 3H) −138.86 61Light Brown dec 359 (400 MHz, DMSO-d₆) ¹⁹F NMR (376 Solid ([M]⁺) 7.69(d, J = 9.8 Hz, 1H), MHz, DMSO-d₆) 7.58-7.47 (m, 2H), 6.54 −111.91, (s,2H), 3.78 (s, 3H) −139.22 62 Light Brown 143-145 407 (400 MHz, DMSO-d₆)¹⁹F NMR (376 Solid ([M+H]⁺), 7.79 (dd, J = 9.6, 1.6 Hz, MHz, DMSO-d₆)1H), 7.72 (dd, J = 8.1, −112.65, 1.6 Hz, 1H), 7.33 (t, J = −139.16 7.9Hz, 1H), 6.53 (s, 2H), 3.78 (s, 3H) 63 White Solid 160-162 332 (400 MHz,DMSO-d₆) ¹⁹F NMR (376 ([M+H]⁺), 13.19 (s, 1H), 9.17 (s, MHz, DMSO-d₆)330 1H), 8.49 (d, J = 8.2 Hz, −66.41, ([M−H]⁻) 1H), 8.05 (d, J = 8.2 Hz,−141.10 1H), 6.63 (s, 2H), 3.80 (s, 3H) 64 White Solid 169-171 363 (300MHz, DMSO-d₆) ([M+H]⁺) 7.62-7.53 (m, 1H), 7.42 (dd, J = 8.7, 1.6 Hz,1H), 7.16 (d, J = 1.8 Hz, 1H), 7.02 (t, J = 73.4 Hz, 1H), 6.70 (s, 2H),3.92 (d, J = 0.8 Hz, 3H) 65 Brown Solid 361 (400 MHz, DMSO-d₆) ¹⁹F NMR(376 ([M+H]⁺) 7.58 (t, J = 7.8 Hz, 1H), MHz, DMSO-d₆) 359 7.50 (d, J =8.4 Hz, 1H), −114.32, ([M−H]⁻) 6.56 (s, 2H), 6.17 (dq, J = −114.37,19.8, 6.4 Hz, 1H), 3.79 −114.39, (s, 3H), 1.73 (dd, J = −114.44, 23.1,6.6 Hz, 3H) −139.01, −139.09, −172.70, −172.75 66 White Solid 118 436(400 MHz, acetone-d₆) ([M+H]⁺), 7.56-7.49 (m, 2H), 7.43 434 7.27 (m,5H), 5.98 (s, ([M−H]⁻) 2H), 5.40 (s, 2H), 3.97 (d, J = 1.1 Hz, 3H), 3.85(s, 3H) 67 Off-White 123-125 393 (300 MHz, CDCl₃) 8.00 Solid ([M+H]⁺),(t, J = 8.5 Hz, 1H), 7.23 391 (m, 3H), 7.15 (dd, J = ([M−H]⁻) 11.1, 2.0Hz, 1H), 4.59 (s, 2H), 4.46 (m, 4H), 1.44 (t, J = 7.1 Hz, 3H) 68 TanSolid (300 MHz, CDCl₃) 7.99 (dd, J = 11.9, 5.1 Hz, 1H), 7.25-7.11 (m,3H), 6.13 (tt, J = 55.0, 3.9 Hz, 1H), 4.74 (d, J = 80.7 Hz, 2H), 4.47(tt, J = 12.3, 6.2 Hz, 2H), 4.27 (td, J = 13.9, 3.9 Hz, 2H), 1.44 (t, J= 7.1 Hz, 3H) 69 Off-White 329.0 (400 MHz, DMSO-d6) ¹⁹F NMR (376Semi-Solid ([M+H]⁺) 7.62-7.51 (m, 2H), 7.42 MHz, DMSO-d₆) (dd, J = 8.3,1.9 Hz, 1H), −112.06, 6.60 (s, 2H), 3.84 (s, 3H), −112.14, 3.78 (s, 3H)−138.59, −138.67 70 Slight Brown 365 (300 MHz, DMSO-d₆) Solid ([M+H]⁺),7.95 (t, J = 8.6 Hz, 1H), 363 7.55 (dd, J = 11.3, 2.0 ([M−H]⁻) Hz, 1H),7.40 (dd, J = 8.5, 2.0 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 6.34 (s, 2H),4.56 (q, J = 9.0 Hz, 2H) ¹⁹F NMR (376 315.47 (400 MHz, CDCl₃) 7.62 −MHz, CDCl₃) 71 White Solid ([M+H]⁺), 7.54 (m, 2H), 7.42 (dd, −107.18,313.99 J = 8.2, 2.0 Hz, 1H), 6.53 −107.26, ([M−H]⁻) (s, 2H), 3.78 (s,3H) −134.44, −134.52 72 Off-White 168-170 331 (400 MHz, DMSO) δ ¹⁹F NMR(376 Solid ([M+H]⁺) 13.38 (s, 1H), 7.81 (d, J = MHz, DMSO) δ 11.1 Hz,1H), 7.73 (s, −115.93, 2H), 6.92 (s, 2H), 2.26 (s, −143.45 3H) 73 WhiteSolid 176-178 237 (400 MHz, DMSO) δ ¹⁹F NMR (376 ([M+H]⁺), 13.58 (s,1H), 7.13 (s, MHz, DMSO) δ 235 ([M−H]⁻) 1H), 2.23 (s, 2H) −140.08 74White Solid 75-77 EIMS m/z (400 MHz, CDCl₃) δ ¹⁹F NMR (376 250 5.35 (s,2H), 3.96 (s, 3H), MHz, CDCl₃) δ 2.33 (s, 3H) −138.81 75 308 (400 MHz,DMSO-d6) δ ¹⁹F NMR ([M+H]⁺) 3.77 (s, 3H), 3.86 (s, 3H), (376 3.92 (s,3H), 6.53 (s, 2H), MHz, DMSO- 6.95 (dd, J = 8.6, 0.8 Hz, d6) δ −141.201H), 8.10 (ddd, J = 8.6, 2.4, 1.1 Hz, 1H), 8.58 (t, J = 2.0 Hz, 1H) 76318 (400 MHz, DMSO-d6) δ ([M+H]⁺) 0.99 (tt, J = 7.6, 2.7 Hz, ¹⁹F NMR4H), 2.17 (tt, J = 7.8, 5.1 (376 Hz, 1H), 3.77 (s, 3H), MHz, DMSO- 3.86(s, 3H), 6.55 (s, 2H), d6) δ −141.19 7.42 (d, J = 8.9 Hz, 1H), 8.00(ddd, J = 8.2, 2.3, 1.2 Hz, 1H), 8.77 (t, J = 2.0 Hz, 1H) 77 304 (400MHz, DMSO-d6) δ ([M+H]⁺) 0.92-1.06 (m, 4H), 2.17 ¹⁹F NMR (376 (tt, J =7.8, 5.1 Hz, 1H), MHz, DMSO- 3.78 (s, 3H), 6.49 (s, 2H), d6) δ −141.737.42 (dd, J = 8.3, 0.9 Hz, 1H), 8.05 (ddd, J = 8.2, 2.2, 1.1 Hz, 1H),8.81 (t, J = 2.0 Hz, 1H), 13.03 (s, 1H) 78 294 (400 MHz, DMSO-d6) δ ¹⁹FNMR (376 ([M+H]⁺) 3.78 (s, 3H), 3.92 (s, 3H), MHz, DMS0- 6.47 (s, 2H),6.95 (dd, J d6) δ −141.78 = 8.7, 0.8 Hz, 1H), 8.15 (ddd, J = 8.7, 2.4,1.1 Hz, 1H), 8.61 (t, J = 2.1 Hz, 1H), 13.02 (s, 1H) 79 331 (400 MHz,DMSO-d6) δ ¹⁹F NMR (376 ([M+H]⁺) 3.78 (s, 3H), 6.54 (s, 2H), MHz DMS0-7.76 (d, J = 8.5 Hz, 1H), d6) δ −140.72 7.84 (dt, J = 8.5, 1.7 Hz, 1H),8.07 (d, J = 1.8 Hz, 1H), 13.10 (s, 1H) 80 331 (400 MHz, DMSO-d6) δ ¹⁹FNMR (376 ([M+H]⁺) 3.78 (s, 3H), 3.87 (s, 3H), MHz, DMSO- 6.61 (s, 2H),7.70-7.88 d6) δ −140.26 (m, 2H), 7.95-8.05 (m,1H) 81 Orange Oil 245 (400MHz, CDCl₃) δ ¹⁹F NMR (376 ([M−H]⁻) 7.06 (s, 1H), 4.59 (s, 2H), MHz,CDCl3) δ 3.97 (s, 3H), 3.88 (s, 3H), −89.99 1.98 (t, J = 18.7 Hz, 3H) 82Orange Oil 231 (400 MHz, DMSO) δ ¹⁹F NMR (376 ([M−H]⁻) 6.99 (s, 1H),6.50 (s, 2H), MHz, DMSO) δ 3.70 (s, 3H), 1.89 (t, J = −87.92 19.1 Hz,3H) 83 White Solid 227 (400 MHz, CDCl₃) δ ¹⁹F NMR (376 ([M−H]⁻) 6.91 (s,1H), 5.59 (dq, J = MHz, CDCl3) δ 47.6, 6.3 Hz, 1H), 4.53 −176.20 (s,2H), 3.97 (s, 3H), 3.87 (s, 3H), 1.62 (dd, J = 24.6, 6.4 Hz, 3H) 84Orange Solid 213 ([M−H]⁻) (400 MHz, DMSO) δ ¹⁹F NMR (376 9.06 (s, 1H),6.82 (s, 1H), MHz, DMSO) δ 6.47 (s, 2H), 5.49 (dq, J = −171.64 47.7, 6.3Hz, 1H), 3.69 (s, 3H), 2.51 (d, J = 24.0 Hz, 1H), 1.52 (dd, J = 24.5,6.4 Hz, 3H) 85 Yellow Oil EIMS m/z ¹H NMR (400 MHz, ¹³C NMR (101 208CDCl₃) δ 6.86 (s, 1H), MHz, CDCl3) δ 6.71 (dd, J = 17.6, 10.9 165.94,Hz, 1H), 5.98 (dd, J = 152.06, 148.02, 17.6, 1.0 Hz, 1H), 5.42 143.34,141.60, (dd, J = 10.9, 1.0 Hz, 136.73, 118.02, 1H), 4.45 (s, 2H), 3.97(s, 108.63, 61.49, 3H), 3.87 (s, 3H) 52.84 86 Brown Solid 178-200 292(300 MHz, ([M+H]⁺) CDCl₃) δ 7.88 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.5Hz, 1H), 6.95 (s, 1H), 5.39 (s, 1H), 4.07 (s, 1H), 3.98 (s, 1H), 2.98(d, J = 5.1 Hz, 1H) 87 Brown Solid 153-154 306 (300 MHz, CDCl₃) δ([M+H]⁺) 7.85 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 7.34 (s,1H), 6.06 (s, 2H), 3.98 (s, 3H), 2.79 (s, 6H) 88 Brown Solid 93-94 369([M−H]⁻) (300 MHz, CDCl₃) δ 7.67 (dd, J = 8.6, 7.7 Hz, 1H), 7.22 (m,1H), 7.11 (d, J = 1.9 Hz, 1H), 5.16 (s, 2H), 4.47 (q, J = 7.1 Hz, 2H),3.96 (d, J = 0.9 Hz, 3H), 2.30 (d, J = 1.7 Hz, 3H), 1.43 (t, J = 7.1 Hz,3H) 89 Yellow Solid 409 (400 MHz, CDCl₃) δ ¹⁹F NMR (376 ([M+H]⁺) 8.02(m, 1H), 7.23 (m, MHz, CDCl₃) 407 1H), 7.16 (m, 16H), 5.20 δ −66.36,([M−H]⁻) (s, 2H), 4.48 (q, J = 7.1 −113.57 Hz, 2H), 3.42 (q, J = 10.0Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H) 91 425 (400 MHz, CDCl₃) δ ¹⁹F NMR (376([M+H]⁺) 7.77-7.84 (m,1H), 7.68- MHz, DMSO- 423 7.77 (m, 2H), 6.80 (s,d6) δ −140.15, ([M−H]⁻) 2H), 3.88 (s, 3H) −115.85. 92 White Solid 233(400 MHz, CDCl₃) δ ¹⁹F NMR (376 ([M+H]⁺) 7.06 (s, 1H), 6.54 (t, J = MHz,CDCl3) 55.4 Hz, 1H), 4.69 (s, δ −114.65 2H), 3.98 (s, 3H), 3.90 (s, 3H)93 White Solid 125-126 345 (400 MHz, CDCl3) δ ¹⁹F NMR (376 ([M+H]⁺),7.77 (dd, J = 28.9, 9.5 MHz, CDCl3) 343 Hz, 2H), 7.47 (m, 1H), δ−115.10, ([M−H]⁻) 5.28 (s, 2H), 3.99 (s, 3H), −143.40 2.35 (s, 3H) 94White Solid 113-117 375 (400 MHz, CDCl₃) δ 19F NMR (376 ([M+H]⁺) 7.27 −7.24 (m, 2H), 5.31 MHz, CDCl3) 373 (s, 2H), 3.98 (d, J = 1.1 δ −127.97,([M−H]⁻) Hz, 3H), 3.96 (s, 3H), −128.06, 2.32 (s, 3H) −140.43, −140.5295 Tan Solid 213 (400 MHz, DMSO-d₆) δ ¹⁹F NMR (376 ([M+H]⁺) 3.73 (s,3H), 5.50 (dd, J = MHz, DMSO- 11.0, 2.2 Hz, 1H), 6.20 d₆) δ −145.09 .(dd, J = 17.3, 2.2 Hz, 1H), 6.35 (s, 2H), 6.83 (ddd, J = 17.3, 10.9, 1.7Hz, 1H), 12.98 (s, 1H). ¹Unless otherwise stated, the mass spectrometrydata are electrospray ionization mass spectrometry (ESIMS).

Example 69 Preparation of Herbicidal Compositions

In the following illustrative compositions, parts and percentages are byweight (wt %).

Emulsifiable Concentrates

Formulation A

WT % Compound 12 26.2 Polyglycol 26-3 5.2 Nonionic emulsifier-(di-sec-butyl)phenylpoly(oxypropylene)block polymer with oxyethylene). Thepolyoxyethelene content is about 12 moles. Witconate P12-20 5.2 (Anionicemulsifier-calcium dodecylbenzene sulfonate- 60 wt. % active) Aromatic100 63.4 (Xylene range aromatic solvent)

Formulation B

WT % Compound 66 3.5 Sunspray 11N (paraffin oil) 40.0 Polyglycol 26-319.0 Oleic acid 1.0 Xylene range aromatic solvent 36.5

Formulation C

WT % Compound 68 13.2 Stepon C-65 25.7 Ethomeen T/25 7.7 Ethomeen T/1518.0 Xylene range aromatic solvent 35.4

These concentrates can be diluted with water to give emulsions ofsuitable concentrations for controlling weeds.

Wettable Powders

Formulation D

WT % Compound 46 26.0 Polyglycol 26-3 2.0 Polyfon H 4.0 Zeosyl 100(Precipitated hydrated SiO₂) 17.0 Barden clay + inerts 51.0

Formulation E

WT % Compound 55 62.4 Polyfon H (sodium salt of lignin 6.0 sulfonate)Sellogen HR (sodium naphthalene 4.0 sulfonate) Zeosyl 100 27.6

The active ingredient is applied to the corresponding carriers and thenthese are mixed and ground to yield wettable powders of excellentwettability and suspension power. By diluting these wettable powderswith water it is possible to obtain suspensions of suitableconcentrations for controlling weeds.

Water Dispersible Granules

Formulation F

WT % Compound 48 26.0 Sellogen HR 4.0 Polyfon H 5.0 Zeosyl 100 17.0Kaolinite clay 48.0

The active ingredient is added to the hydrated silica, which is thenmixed with the other ingredients and ground to a powder. The powder isagglomerated with water and sieved to provide granules in the range of−10 to +60 mesh. By dispersing these granules in water it is possible toobtain suspensions of suitable concentrations for controlling weeds.

Granules

Formulation G

WT % Compound 58 5.0 Celetom MP-88 95.0

The active ingredient is applied in a polar solvent such as N-methylpyrrolidinone, cyclohexanone, gamma-butyrolactone, etc. to the CeletomMP 88 carrier or to other suitable carriers. The resulting granules canbe applied by hand, granule applicator, airplane, etc. in order tocontrol weeds.

Formulation H

WT % Compound 28 1.0 Polyfon H 8.0 Nekal BA 77 2.0 Zinc Stearate 2.0Barden Clay 87.0

All materials are blended and ground to a powder, then water is addedand the clay mixture is stirred until a paste is formed. The mixture isextruded through a die to provide granules of proper size.

Example 70 Evaluation of Postemergent Herbicidal Activity

Post-Emergent Test I:

Seeds or nutlets of the desired test plant species were planted in SunGro Metro-Mix® 360 planting mixture, which typically has a pH of 6.0 to6.8 and an organic matter content of about 30 percent, in plastic potswith a surface area of 64 square centimeters. When required to ensuregood germination and healthy plants, a fungicide treatment and/or otherchemical or physical treatment was applied. The plants were grown for7-21 d in a greenhouse with an approximate 15 h photoperiod which wasmaintained at about 23-29° C. during the day and 22-28° C. during thenight. Nutrients and water were added on a regular basis andsupplemental lighting was provided with overhead metal halide 1000-Wattlamps as necessary. The plants were employed for testing when theyreached the first or second true leaf stage.

A weighed amount, determined by the highest rate to be tested, of eachtest compound was placed in a 25 mL glass vial and was dissolved in 4 mLof a 97:3 v/v mixture of acetone and DMSO to obtain concentrated stocksolutions. If the test compound did not dissolve readily, the mixturewas warmed and/or sonicated. The concentrated stock solutions obtainedwere diluted with 20 mL of an aqueous mixture containing acetone, water,isopropyl alcohol, DMSO, Atplus 411F crop oil concentrate, and Triton®X-155 surfactant in a 48.5:39:10:1.5:1.0:0.02 v/v ratio to obtain spraysolutions containing the highest application rates. Additionalapplication rates were obtained by serial dilution of 12 mL of the highrate solution into a solution containing 2 mL of 97:3 v/v mixture ofacetone and DMSO and 10 mL of an aqueous mixture containing acetone,water, isopropyl alcohol, DMSO, Atplus 411F crop oil concentrate, andTriton X-155 surfactant in a 48.5:39:10:1.5:1.0:0.02 v/v ratio to obtain½×, ¼×, ⅛× and 1/16× rates of the high rate. Compound requirements arebased upon a 12 mL application volume at a rate of 187 liters perhectare (L/ha). Formulated compounds were applied to the plant materialwith an overhead Mandel track sprayer equipped with 8002E nozzlescalibrated to deliver 187 L/ha over an application area of 0.503 squaremeters at a spray height of 18 inches (43 cm) above the average plantcanopy height. Control plants were sprayed in the same manner with thesolvent blank.

The treated plants and control plants were placed in a greenhouse asdescribed above and watered by subirrigation to prevent wash-off of thetest compounds. After 14 d, the condition of the test plants as comparedwith that of the untreated plants was determined visually and scored ona scale of 0 to 100 percent where 0 corresponds to no injury and 100corresponds to complete kill. Some of the compounds tested, applicationrates employed, plant species tested, and results are given in Table 3and Table 8.

TABLE 3 Post-emergent Test I Herbicidal Activity Application CompoundRate (g Visual Growth Reduction (%)-14 Days after Application Numberai/ha) ABUTH CHEAL EPHHL ECHCG CYPES ORYSA ZEAMX  1 280 100 100 100 0 00 0  2 280 90 90 95 0 0 0 0  3 140 100 100 100 0 0 0 10  4 140 80 100100 0 0 0 0  5 70 100 100 100 80 20 0 60  6 140 60 100 100 0 20 5 0  7140 90 100 95 0 0 0 0  8 280 25 30 90 0 0 0 0 10 280 100 100 100 0 0 025 11 140 100 100 100 100 50 12 80 12 280 0 70 0 0 0 0 0 13 280 0 90 700 0 0 0 19 70 85 100 100 75 90 0 70 20 70 85 100 100 80 50 0 80 21 70 85100 100 50 70 0 50 22 140 60 100 100 90 50 0 70 23 140 70 100 100 80 1000 70 24 140 60 65 100 50 100 0 75 25 140 70 90 100 85 100 0 70 26 140 1090 100 55 50 0 75 27 140 60 90 100 60 100 0 70 28 70 70 100 100 80 40 570 30 140 50 100 100 0 100 0 70 31 140 100 100 100 95 100 15 85 32 14095 100 100 90 100 0 75 33 140 100 100 100 80 100 0 70 34 140 100 100 100100 100 10 90 35 140 75 100 100 80 100 0 70 36 140 100 100 100 0 100 060 37 140 55 100 100 100 100 0 75 38 140 85 90 100 10 50 0 75 39 70 80100 100 80 100 0 75 40 140 80 100 100 50 100 0 70 41 140 80 100 100 0100 0 70 42 140 60 90 100 0 10 0 75 43 140 90 100 100 80 50 0 70 44 14050 100 0 0 100 0 15 45 140 100 100 100 100 100 0 65 46 140 100 100 10015 0 0 0 47 140 100 100 100 100 100 45 85 48 140 90 100 100 90 100 0 8049 140 100 100 100 100 100 25 90 50 140 90 90 100 70 100 30 75 51 70 090 100 0 0 0 0 52 140 — 100 100 60 100 0 50 53 140 80 100 0 80 100 15 7554 70 90 90 100 90 100 5 85 55 132 85 90 100 100 100 10 80 56 140 80 90100 100 50 10 75 57 70 85 100 100 90 70 0 75 58 280 60 80 65 0 0 0 10 5970 80 100 100 100 50 5 70 60 70 60 90 100 95 50 15 75 61 140 80 100 10095 100 10 75 62 140 15 100 100 100 50 8 75 63 140 90 100 100 95 100 5080 64 280 50 85 95 0 0 0 10 65 140 100 100 100 65 100 0 70 66 140 100100 100 60 100 0 80 67 280 25 50 35 0 0 0 0 68 180 100 90 100 0 90 0 1069 70 85 0 100 30 100 0 10 70 280 50 25 100 0 85 0 75 71 70 80 90 100 85100 0 70 72 140 80 100 100 0 90 30 60 73 140 10 10 50 0 0 0 0 74 140 0 00 0 0 0 0 75 140 90 85 85 0 95 0 85 76 140 85 80 97 0 95 0 50 77 140 8075 95 85 90 65 95 78 70 80 97 80 85 80 50 80 79 70 80 100 95 70 90 15 8080 70 70 85 90 0 93 0 50 81 140 10 80 60 0 0 0 0 82 140 20 85 80 0 0 0 083 140 0 0 0 0 0 0 0 84 140 10 30 0 0 0 0 0 86 280 40 95 50 NT 0 0 0 87140 90 90 100 40 90 0 0 88 140 100 100 100 100 60 0 80 89 140 30 70 90 00 0 0 92 140 40 95 70 0 0 0 0 93 140 30 90 50 0 0 0 0 94 140 60 85 65 00 0 0 95 140 0 60 30 0 0 0 0 ABUTH: velvetleaf (Abutilon theophrasti)CHEAL: lambsquarters (Chenopodium album) EPHHL: wild poinsettia(Euphorbia heterophylla) ECHCG: barnyardgrass (Echinochloa crus-galli)CYPES: yellow nutsedge (Cyperus esculentus) ORYSA: rice (Oryza sativa)ZEAMX: corn (Zea mays) g ai/ha: grams active ingredient per hectare NT:not tested

By applying the well-accepted probit analysis as described by J. Berksonin Journal of the American Statistical Society, 48, 565 (1953) and by D.Finney in “Probit Analysis” Cambridge University Press (1952), the abovedata can be used to calculate GR₂₀, GR₅₀ and GR₈₀ values, which aredefined as growth reduction factors that correspond to the effectivedose of herbicide required to kill or control 20 percent, 50 percent or80 percent, respectively, of a target plant.

TABLE 4 Herbicidal Activity of various compounds with selectivity tomaize Application Visual Growth Reduction (%)- Compound Rate (g 14 Daysafter Application Number ai/ha) CHEAL ABUTH POLCO ZEAMX TRZAS  1 280 100100 100 0 0 140 100 95 95 0 0 70 95 95 100 0 0 35 90 85 100 0 0 17.5 9040 100 0 0 GR₂₀ <17.5 10.5 <17.5 >280 >280 GR₅₀ <17.5 19.4<17.5 >280 >280 GR₈₀ <17.5 35.9 <17.5 >280 >280  6 140 100 85 100 20 5070 100 85 100 10 45 35 100 80 NT 0 15 17.5 100 75 100 0 0 8.75 90 50 0 00 GR₂₀ <8.75 <8.75 10.7 132 47.5 GR₅₀ <8.75 6.42 12.4 >140 109 GR₈₀<8.75 38.1 14.3 >140 >140 45 140 100 100 100 65 65 70 100 100 100 60 6035 100 100 100 55 55 17.5 100 100 100 50 20 8.75 90 90 100 50 10 GR₂₀<8.75 <8.75 <8.75 <8.75 14.3 GR₅₀ <8.75 <8.75 <8.75 12.4 53.5 GR₈₀ <8.75<8.75 <8.75 >140 >140 46 280 100 100 100 0 75 140 100 100 100 0 70 70100 95 100 0 40 35 95 85 90 0 20 17.5 90 80 80 0 15 GR₂₀ <17.5 <17.5<17.5 >280 27.1 GR₅₀ <17.5 <17.5 <17.5 >280 91.7 GR₈₀ <17.5 19.718.6 >280 310 47 140 100 100 100 85 50 70 100 100 100 80 45 35 100 95100 75 30 17.5 100 95 100 55 15 8.75 90 90 100 40 0 GR₂₀ <8.75 <8.75<8.75 <8.75 30.6 GR₅₀ <8.75 <8.75 <8.75 12.6 98.6 GR₈₀ <8.75 <8.75 <8.7574.1 >140 CHEAL: lambsquarters (Chenopodium album) ABUTH: velvetleaf(Abutilon theophrasti) POLCO: buckwheat, wild (Polygonum convolvulus)ZEAMX: corn (Zea mays) TRZAS: wheat, spring (Triticum aestivum) g ai/ha:grams active ingredient per hectare NT: Not tested GR₂₀: Growthreduction of 20% of plant growth GR₅₀: Growth reduction of 50% of plantgrowth GR₈₀: Growth reduction of 80% of plant growth

Example 71 Evaluation of Preemergent Herbicidal Activity

Seeds of the desired test plant species were planted in a soil matrixprepared by mixing a loam soil (43 percent silt, 19 percent clay, and 38percent sand, with a pH of about 8.1 and an organic matter content ofabout 1.5 percent) and sand in a 70 to 30 ratio. The soil matrix wascontained in plastic pots with a surface area of 113 square centimeters.When required to ensure good germination and healthy plants, a fungicidetreatment and/or other chemical or physical treatment was applied.

A weighed amount, determined by the highest rate to be tested, of eachtest compound was placed in a 25 mL glass vial and was dissolved in 6 mLof a 97:3 v/v (volume/volume) mixture of acetone and DMSO to obtainconcentrated stock solutions. If the test compound did not dissolvereadily, the mixture was warmed and/or sonicated. The stock solutionsobtained were diluted with 18 mL of a 0.1% v/v aqueous solution ofTween® 20 surfactant to obtain spray solutions containing the highestapplication rate. Additional application rates were obtained by serialdilution of 12 mL of the high rate solution into a solution containing 3mL of 97:3 v/v mixture of acetone and DMSO and 9 mL of the 0.1% v/vaqueous solution of Tween® 20 surfactant to obtain ½×, ¼×, ⅛× and 1/16×rates of the high rate. Compound requirements are based upon a 12 mLapplication volume at a rate of 187 L/ha. Formulated compounds wereapplied to the plant material with an overhead Mandel track sprayerequipped with 8002E nozzles calibrated to deliver 187 L/ha over anapplication area of 0.503 square meters at a spray height of 18 inches(43 cm) above the soil surface. Control plants were sprayed in the samemanner with the solvent blank.

The treated pots and control pots were placed in a greenhouse maintainedwith an approximate 15 hour photoperiod and temperatures of about 23-29°C. during the day and 22-28° C. during the night. Nutrients and waterwere added on a regular basis and supplemental lighting was providedwith overhead metal halide 1000-Watt lamps as necessary. The water wasadded by top-irrigation. After 20-22 days, the condition of the testplants that germinated and grew as compared with that of the untreatedplants that emerged and grew was determined visually and scored on ascale of 0 to 100 percent where 0 corresponds to no injury and 100corresponds to complete kill or no emergence. Some of the compoundstested, application rates employed, plant species tested, and resultsare given in Table 5.

TABLE 5 Pre-emergent Test I Herbicidal Activity Com- Application VisualGrowth Reduction (%)- pound Rate, (g 21 Days after Application Numberai/ha) CHEAL AMARE EPHHL SETFA ZEAMX 46 140 95 95 100 100 0 CHEAL:lambsquarters (Chenopodium album) AMARE: pigweed, redroot (Amaranthusretroflexus) EPHHL: poinsettia, wild (Euphorbia heterophylla) SETFA:foxtail, giant (Setaria faberi) ZEAMX: corn (Zea mays) g ai/ha: gramsactive ingredient per hectare

Example 72 Evaluation of Foliar-Applied Postemergence HerbicidalActivity in Direct Seeded Rice

Seeds or nutlets of the desired test plant species were planted in asoil matrix prepared by mixing a loam soil (43 percent silt, 19 percentclay, and 38 percent sand, with a pH of about 8.1 and an organic mattercontent of about 1.5 percent) and river sand in an 80 to 20 ratio. Thesoil matrix was contained in plastic pots with a surface area of 139.7cm². When required to ensure good germination and healthy plants, afungicide treatment and/or other chemical or physical treatment wasapplied. The plants were grown for 10-17 d in a greenhouse with anapproximate 14-h photoperiod which was maintained at about 29° C. duringthe day and 26° C. during the night. Nutrients and water were added on aregular basis and supplemental lighting was provided with overhead metalhalide 1000-Watt lamps as necessary. The plants were employed fortesting when they reached the second or third true leaf stage.

Treatments consisted of compounds 45, 34, and 66. Weighed amounts oftechnical compounds were placed in individual 25 mL glass vials anddissolved in 8 mL of 97:3 v/v acetone-DMSO to obtain stock solutions. Ifthe test compound did not dissolve readily, the mixture was warmedand/or sonicated. The spray application solutions were prepared byremoving 4 mL of the stock solution and diluting with 4 mL of 97:3 v/vacetone-DMSO and continued serial dilution to obtain ½×, ¼×, ⅛×, and1/16× rates of the high rate. Spray solutions were diluted to theappropriate final concentrations with the addition of 8 mL of an aqueousmixture of 1.875% (v/v) Agri-dex crop oil concentrate. The final 12-mLspray solutions each contained 1.25% (v/v) Agri-dex crop oilconcentrate, 32.3% acetone, and 1.0% DMSO. Compound requirements arebased upon a 12 mL application volume at a rate of 187 L/ha. Spraysolutions were applied to the plant material with an overhead Mandeltrack sprayer equipped with 8002E nozzles calibrated to deliver 187 L/haover an application area of 0.503 square meters (m²) at a spray heightof 18 inches (43 cm) above average plant canopy height. Control plantswere sprayed in the same manner with the solvent blank.

The treated plants and control plants were placed in a greenhouse asdescribed above and watered by sub-irrigation to prevent wash-off of thetest compounds. After approximately 3 weeks, the condition of the testplants, compared with that of the untreated plants, was determinedvisually and scored on a scale of 0 to 100 percent where 0 correspondsto no injury and 100 corresponds to complete kill.

By applying the well-accepted probit analysis as described by J. Berksonin Journal of the American Statistical Society, 48, 565 (1953) and by D.Finney in “Probit Analysis” Cambridge University Press (1952) or byplotting the mean data and fitting a logarithmic curve to the portion ofthe data where there was a dose response using Microsoft Excel®, theabove data can be used to calculate GR₅₀ and GR₉₀ values, which aredefined as growth reduction factors that correspond to the effectivedose of herbicide required to kill or control 50 percent or 90 percent,respectively, of a target plant.

Some of the application rates and ratios employed, plant species tested,and results are given in Table 6.

TABLE 6 Activity of Herbicidal Compounds in Direct Seeded Rice (meanvisual injury may represent data gathered in multiple trials). MeanVisual Injury (%)-21 Days After Application ORYSA Compound Rate (g‘Clearfield ORYSA Number ae/ha) AESSE SEBEX LEFCH ECHCG ECHCO BRAPPCYPES CYPIR CYPDI SCPJU 171’ ‘Wells’ 45 70 100 100 60 100 100 98 95 100100 100 47 23 35 100 100 42 98 98 95 99 100 100 100 35 10 17.5 100 10020 95 95 95 85 100 98 100 15 0 8.75 100 100 0 92 88 80 78 97 97 100 12 04.38 100 100 3 92 80 72 73 95 75 72 0 0 GR₅₀ <4.38 <4.38 53.5 <4.38<4.38 <4.38 <4.38 <4.38 <4.38 <4.38 >70 >70 GR₉₀ <4.38 <4.38 >70 <4.3812.9 22.0 27.1 <4.38 8.8 6.9 >70 >70 34 70 100 100 37 95 98 93 100 100100 100 22 7 35 100 100 40 98 97 92 95 100 100 100 23 8 17.5 100 100 3096 92 93 85 98 100 100 12 3 8.75 100 100 17 93 80 77 73 97 95 100 3 04.38 100 100 0 93 70 73 73 83 87 100 0 0 GR₅₀ <4.38 <4.38 >70 <4.38<4.38 <4.38 <4.38 <4.38 <4.38 <4.38 >70 >70 GR₉₀ <4.38 <4.38 >70 <4.3818.6 30.2 27.4 6.7 5.8 <4.38 >70 >70 66 70 100 100 40 95 94 93 95 99 97100 8 0 35 100 100 26 97 94 87 94 100 99 100 6 0 17.5 100 99 32 96 93 90100 100 100 2 2 8.75 100 99 15 95 89 83 93 99 96 100 1 0 4.38 100 90 786 80 72 67 81 91 88 0 0 2.19 53 0 78 62 53 60 43 70 100 0 0 GR₅₀ <4.38<2.19 >70 <42.19 <2.19 <2.19 <2.19 2.4 <2.19 <42.19 >70 >70 GR₉₀ <4.385.8 >70 8.3 11.6 34.4 13.1 6.4 6.6 4.9 >70 >70 AESSE = Aeschynomenesensitiva SW./L. (sensitive jointvetch) BRAPP = Brachiaria platyphylla(GRISEB.) NASH (broadleaf signalgrass) CYPDI = Cyperus difformis L.(small-flower flatsedge) CYPES = Cyperus esculentus L. (yellow nutsedge)CYPIR = Cyperus iria L. (rice flatsedge) ECHCG = Echinochloa crus-galli(L.) P.BEAUV. (barnyardgrass) ECHCO = Echinochloa colonum (L.) LINK(junglerice) LEFCH = Leptochloa chinensis (L.) NEES (Chinesesprangletop) SCPJU = Scirpus juncoides ROXB. (Japanese bulrush) SEBEX =Sesbania exaltata (RAF.) CORY/RYDB. (hemp sesbania) ORYSA = Oryza sativa‘Clearfield 171’ (rice) ORYSA = Oryza sativa ‘Wells’ (rice) g ae/ha =gram acid equivalent per hectare DAA = days after application

Example 73 Evaluation of in-Water Applied Herbicidal Activity inTransplanted Paddy Rice

Weed seeds or nutlets of the desired test plant species were planted inpuddled soil (mud) prepared by mixing a non-sterilized mineral soil (28percent silt, 18 percent clay, and 54 percent sand, with a pH of about7.3 to 7.8 and an organic matter content of about 1.0 percent) and waterat a ratio of 100 kilograms (kg) of soil to 19 liters (L) of water. Theprepared mud was dispensed in 250 mL aliquots into 480 mL non-perforatedplastic pots with a surface area of 86.59 cm² leaving a headspace of 2.5to 3 cm in each pot.

Rice seeds were planted in Sun Gro MetroMix 306 planting mixture, whichtypically has a pH of 6.0 to 6.8 and an organic matter content of about30 percent, in plastic plug trays. Seedlings at the second or third leafstage of growth were transplanted into 650 mL of mud contained in 960 mLnon-perforated plastic pots with a surface area of 86.59 cm² four daysprior to herbicide application.

The paddy was created by filling the 2.5 to 3 cm headspace of the potswith water. When required to ensure good germination and healthy plants,a fungicide treatment and/or other chemical or physical treatment wasapplied. The plants were grown for 4-14 d in a greenhouse with anapproximate 14-h photoperiod which was maintained at about 29° C. duringthe day and 26° C. during the night. Nutrients were added as Osmocote(17:6:10, Nitrogen:Phosphorus:Potassium (N:P:K)+minor nutrients) at 2grams (g) per cup. Water was added on a regular basis to maintain thepaddy flood, and supplemental lighting was provided with overhead metalhalide 1000-Watt lamps as necessary. The plants were employed fortesting when they reached the second or third true leaf stage.

Treatments consisted of compounds 45, 34, and 66. For technical gradecompounds, a weighed amount, determined by the highest rate to betested, was placed in an individual 120 mL glass vial and was dissolvedin 20 mL of acetone to obtain concentrated stock solutions. If the testcompound did not dissolve readily, the mixture was warmed and/orsonicated. The concentrated stock solutions obtained were diluted with20 mL of an aqueous mixture containing 2.5% Agri-dex crop oilconcentrate (v/v). Applications were made by injecting an appropriateamount of the stock solution into the aqueous layer of the paddy.Control plants were treated in the same manner with the solvent blank.All treated plant material received the same concentration of acetoneand crop oil concentrate.

The treated plants and control plants were placed in a greenhouse asdescribed above and water was added as needed to maintain a paddy flood.After approximately 3 weeks, the condition of the test plants, comparedwith that of the untreated plants, was determined visually and scored ona scale of 0 to 100 percent where 0 corresponds to no injury and 100corresponds to complete kill.

By applying the well-accepted probit analysis as described by J. Berksonin Journal of the American Statistical Society, 48, 565 (1953) and by D.Finney in “Probit Analysis” Cambridge University Press (1952) or byplotting the mean data and fitting a logarithmic curve to the portion ofthe data where there was a dose response using Microsoft Excel®, theabove data can be used to calculate GR₅₀ and GR₉₀ values, which aredefined as growth reduction factors that correspond to the effectivedose of herbicide required to kill or control 50 percent or 90 percent,respectively, of a target plant.

Some of the compounds tested, application rates employed, plant speciestested, and results are given in Tables 7 and 8.

TABLE 7 Activity of Herbicidal Compounds in Transplanted Paddy Rice(mean visual injury may represent data gathered in multiple trials).Mean Visual Injury (%)-21 Days After Application Compound Rate (g ORYSAORYSA Number ae/ha) MOOVA ECHCG CYPDI SCPJU ‘M202’ ‘Wells’ 45 140 100100 100 100 12 7 70 100 100 100 100 0 0 35 100 30 100 93 0 0 17.5 100 0100 63 0 0 8.75 100 0 67 10 0 0 GR₅₀ <8.75 38.4 <8.75 16.8 >140 >140GR₉₀ <8.75 66.8 14.2 42.4 >140 >140 34 140 100 100 100 100 8 5 70 100 98100 100 7 0 35 100 90 100 100 0 0 17.5 100 7 100 90 0 0 8.75 100 0 10067 0 0 GR₅₀ <8.75 25.4 <8.75 <8.75 >140 >140 GR₉₀ <8.75 52.9 <8.7521.1 >140 >140 66 140 100 100 100 100 17 5 70 100 99 100 100 0 0 35 10086 100 100 0 0 17.5 100 57 100 98 0 0 8.75 100 6 94 94 0 0 4.38 100 3 4878 0 2.19 0 0 0 35 0 GR₅₀ <4.38 17.4 4.5 2.8 >140 >140 GR₉₀ <4.38 53.78.2 7.1 >140 >140 CYPDI = Cyperus difformis L. (small-flower flatsedge)ECHCG = Echinochloa crus-galli (L.) P.BEAUV. (barnyardgrass) MOOVA =Monochoria vaginalis (BURM.f.) C.PRESL ex KUNTH (monochoria) SCPJU =Scirpus juncoides ROXB. (Japanese bulrush) ORYSA = Oryza sativa ‘M202’(rice) ORYSA = Oryza sativa ‘Wells’ (rice) g ae/ha = gram acidequivalent per hectare DAA = days after application

TABLE 8 Activity of Herbicidal Compounds in Transplanted Paddy Rice(mean visual injury may represent data gathered in multiple trials).Compound Rate (g Mean Visual Injury (%)-21 Days After Application Numberae/ha) LIDDU LEFCH ECHOR CYPRO FIMMI 66 70 100 100 95 100 100 35 100 1689 100 100 17.5 100 0 21 100 73 8.75 100 0 8 100 36 4.38 100 0 0 65 102.19 0 0 0 0 GR₅₀ <4.38 40.9 21.2 <4.38 10.3 GR₉₀ <4.38 71.2 59.0 7.229.7 CYPRO = Cyperus rotundus L. (purple nutsedge) ECHOR = Echinochloacrus-galli P.B. var. oryzoides (VAS.) OHWI (early watergrass) FIMMI =Fimbristylis miliacea (L.) VAHL (globe fringerush) LEFCH = Leptochloachinensis (L.) NEES (Chinese sprangletop) LIDDU = Lindernia dubia (L.)PENNELL (low falsepimpernel) ORYSA Oryza sativa ‘M202’ (rice) ORYSA =Oryza sativa ‘Wells’ (rice) g ae/ha = gram acid equivalent per hectareDAA = days after application

What is claimed is:
 1. A compound of the Formula II

wherein Q represents H or I; and Y represents a phenyl group substitutedwith one to four substitutents independently selected from halogen,C₁-C₆ alkoxy or C₁-C₆ haloalkyl; or a C₁-C₁₂ ester thereof.
 2. Thecompound of claim 1, wherein the compound is:


3. The compound of claim 1, wherein the compound is a compound ofFormula II or a C₁-C₆ alkyl ester or benzyl ester thereof.